As interest in γδ T cells grows rapidly, what key points are emerging, and where is caution warranted? γδ T cells fulfill critical functions, as reflected in associations with vaccine responsiveness and cancer survival in humans and ever more phenotypes of γδ T cell–deficient mice, including basic physiological deficiencies. Such phenotypes reflect activities of distinct γδ T cell subsets, whose origins offer interesting insights into lymphocyte development but whose variable evolutionary conservation can obfuscate translation of knowledge from mice to humans. By contrast, an emerging and conserved feature of γδ T cells is their “adaptate” biology: an integration of adaptive clonally-restricted specificities, innate tissue-sensing, and unconventional recall responses that collectively strengthen host resistance to myriad challenges. Central to adaptate biology are butyrophilins and other γδ cell regulators, the study of which should greatly enhance our understanding of tissue immunogenicity and immunosurveillance and guide intensifying clinical interest in γδ cells and other unconventional lymphocytes.

Running like a central artery through the biology of γδ T cells is one major question, namely, what unique host benefit is contributed by a highly conserved third lineage of cells that, together with B cells and αβ T cells, has somatically diversified surface receptors (1)? The question’s significance was starkly reinforced when a wholly unrelated molecular mechanism in jawless vertebrates (agnathans) was found to likewise diversify three cell lineages (2).

For 25 years, γδ cells have highlighted atypical lymphoid effector functions, such as keratinocyte growth factor production (3), but their primary role may be to expand the breadth of immune responsiveness. Unlike αβ T cells, γδ T cells are not limited to recognition of peptides presented by MHC proteins, lipids presented by CD1, and metabolites presented by MR1, although this does not exclude such reactivities from their repertoire (4). The few TCR γδ Ags so far characterized are structurally diverse, including MHC, CD1, several other cell-bound Ags, histidyl-tRNA synthetase, and haptens that may modify cell surface proteins (5, 6). This breadth seemingly reflects an enormous potential for diversity, particularly of TCRδ (7). Moreover, this potential has been further increased in Xenopus by inclusion into the TCRδ locus of Ig–VH gene segments (8) and in marsupials and sharks by the generation of TCRδ-based 3-Ig-domain receptor chains that pair with TCRγ to form TCRμ and new Ag receptor–TCR molecules, respectively (9, 10). Thus, a major challenge is to reconcile roles for γδ T cells in immunosurveillance with an unparalleled potential for diversity.

Additionally, γδ T cells may expand the spatial and temporal ranges of immune responsiveness by being activated in anatomical sites and/or ontogenetic periods not well served by B cells and αβ T cells (11). Although gray short-tailed opossums may be an exception (12), many γδ T cell subsets mature prior to αβ T cell maturation (13), with further examples continuing to emerge in mice and in humans (1416). Predictably, therefore, some γδ T cell phenotypes are most overt prior to adulthood (17, 18).

Furthermore, the rapid response kinetics of γδ T cells (19) may critically regulate tissue immunogenicity by altering the local milieu so as to accommodate time-delayed adaptive responses of B cells and αβ T cells while promoting key elements of tissue repair and regeneration (20). Conversely, dysregulation of such activities might fuel inflammatory pathologic conditions, potentially underpinning ever more causal implications of murine γδ T cells in experimental allergic encephalomyelitis (a mouse model of multiple sclerosis), type I diabetes, skin inflammation, and cancer (2126).

Notwithstanding these possibilities, our perspectives on how γδ T cells expand immunological range will likely require us to think more laterally about the host response to infection and tissue dysregulation. To illustrate this, we shall consider emerging data depicting three modes of γδ T cell response (Fig. 1), none of which is easily accommodated by today’s immunology textbooks.

FIGURE 1.

Mouse and human γδ T cells display at least three types of response: durable adaptive clonal expansion of γδ T cells, durable quasi-adaptive expansions, and durable innate repertoire selection.

FIGURE 1.

Mouse and human γδ T cells display at least three types of response: durable adaptive clonal expansion of γδ T cells, durable quasi-adaptive expansions, and durable innate repertoire selection.

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Adaptive responses.

Recent analyses of human peripheral blood and liver revealed large, durable, subject-specific expansions, commonly dominated by a few highly diverse γδ TCRs. Moreover, the expansions were enriched in CD27loCX3CR1+ granzyme-expressing cells, consistent with clonal naive-to-effector differentiation, a signature of adaptive immunity (2729).

The clones’ specificities have yet to be deduced, but, given the potential for diversity in TCRγδ, they could be reasonably expected to include microbe-specific determinants reflecting subject-specific environmental exposures. Potentially consistent with this, hematopoietic stem cell transplantation patients displayed striking patient-specific clonal γδ T cell expansions coincident with CMV reactivation, particularly when γδ T cell reconstitution preceded αβ T cell reconstitution (30). Likewise, human monoclonal or oligoclonal γδ T cell expansions were associated with vertical CMV transmission in utero (31).

CMV is a major immunological driver, eliciting multifaceted, multilayered responses including adaptive NK cells and CMV-specific CD8+ T cells. Hence, a γδ T cell contribution to the CMV response would seem plausible. Indeed, although neither TCRαβ-deficient nor TCRγδ-deficient mice showed impaired responses to CMV infection, mice lacking both T cell types were lethally susceptible (32). Hence, γδ T cell responses to CMV might be particularly important when αβ T cells are impaired, potentially explaining γδ T cell expansions either following transplantation or in utero. Moreover, durable clonal expansions of TCRγδ+ effector cells in healthy human subjects might reflect transient immune deficiencies caused, for example, by sporadic holes in the TCRαβ repertoire.

Consistent with this perspective, overt γδ T cell expansions occurred in heavily immunosuppressed solid organ transplant recipients displaying reduced CMV disease and relatively few incidences of immunosuppression-associated cancer (33, 34). The isolated TCRγδ+ clones lysed CMV-infected cells and could limit human tumor xenograft growth in mice, and, as in hematopoietic stem cell transplantation, they were subject-specific, evoking adaptive immunity to discrete stimuli. However, rather than being CMV-reactive, the first such clone to be characterized expressed a human Vγ4Vδ5 TCR specific for epithelial protein C receptor (EPCR), a CD1-like protein that can be upregulated by CMV infection and cell transformation (6, 35).

With current knowledge, this adaptive response seems puzzling: how did EPCR-reactive cells avoid immunological tolerance of self? How was their expansion favored versus the potential expansion of γδ cell clones with different specificities (e.g., CMV or self)? How do they finely distinguish virus-infected and/or transformed cells from healthy cells? And ultimately, how do they confer host benefit? Moreover, the same questions pertain to other self-reactive γδ T cells, including a human glioblastoma-reactive clone specific for annexin A2, whose surface expression is likewise promoted by CMV (36).

This puzzling scenario also arose in Lyme disease, for which the etiologic agent is Borrelia burgdorferi. Relative to wild-type mice, Borrelia-infected TCRδ−/− mice display increased bacterial burden and cardiac inflammation, associated with greatly diminished αβ T cell and B cell expansions and reduced anti-Borrelia serum Abs, cytokines, and chemokines (37). Seemingly consistent with this important role of γδ T cells, human Τ cells expressing the Vδ1 gene segment were expanded in inflamed synovial joints of patients with Lyme disease. However, rather than being Borrelia-reactive, the expanded cells were responsive to myelomonocytic cells making TLR-dependent responses to Borrelia (38), and their Vδ1 TCRs bound to activated, uninfected monocytes and lymphocytes (R. Budd, personal communication).

In sum, seemingly prototypic adaptive responses have so far identified self-reactive rather than pathogen-specific γδ cells, albeit that such studies are in their infancy. Assuredly, not all TCRγδ reactivities will be self-reactive, particularly in calves and lambs, which harbor high numbers of circulating γδ T cells and in which vaccine-induced γδ responses have been reported (39). Furthermore, subsets of human, mouse, and bovine γδ T cells showed Ag-driven effector differentiation and IL-17 production in response to the microbial Ags, including PE (40, 41). This notwithstanding, we currently lack a clear physiologic natural history for an adaptive γδ T cell response spanning the cellular means of Ag exposure, drivers of clonal expansion, functional benefit to the host, and commitment to memory. It is, therefore, possible that, despite their potential for immense diversity, the uniqueness of γδ T cells may sit outside of conventional, microbe-specific adaptive immunity.

Quasi-adaptive responses.

Following oral infection with an epithelial-tropic strain of Listeria monocytogenes, dramatic expansions of mouse γδ T cells were observed in the mesenteric lymph nodes (LN) and intestinal lamina propria (LP) (42). The expanded cells failed to recirculate following parabiosis, evoking a key component of immunological memory, namely, the cells’ durable relocation to anatomical sites responsive to rechallenge (42). Consistent with this, expanded mesenteric LN and LP cells were rapidly reactivated by oral L. monocytogenes reinfection but not by oral Salmonella (live or attenuated) (42). The expanded γδ cells were the major producers of IL-17A, the blockade of which increased bacterial burden and delayed clearance. Hence, the response phenocopied host-protective adaptive immunity (42), simultaneously asserting that γδ T cells are not merely a first line of defense.

However, rather than being dominated by L. monocytogenes–specific clones, the expanded γδ T cells were not diverse, primarily expressing a Vγ6Vδ1 TCR present at steady state in the lungs and uterus of mice never exposed to L. monocytogenes and commonly found in other infectious and noninfectious scenarios (43) (below). In sum, microbe-specific γδ T cells were again difficult to identify, even in the setting of a host-beneficial, γδ-dependent effector response to an Ag-rich pathogen.

Instead, the prospect that Vγ6Vδ1+ T cell responses were driven by an anatomical context of infection more than by specific microbial determinants was suggested by the cells’ failure to expand in the guts, spleens, or livers of mice infected with L. monocytogenes i.v. despite major hepatic bacterial accumulations (42). Pathophysiologic context might also explain the selective occurrences of such responses: thus, murine Vγ6Vδ1+ expansions were also provoked by repeated inhalations of Bacillus subtilis, whereupon they produced IL-17A that helped clear pneumonitis and resolve fibrosis (43). However, Vγ6Vδ1+ cells did not expand in Saccharopolyspora rectivirgula–induced pulmonary fibrosis, during which IL-17A was produced by expanded CD4+ Th17 cells (43). Clearly, we need a molecular explanation of how context rather than adaptive specificity can drive host-beneficial, tissue-specific γδ T cell expansions to many but not all microbial exposures.

A challenge in linking specificity to host benefit likewise pertains to malaria. The limited protection of humans induced by repeated vaccination with malarial sporozoites was associated with γδ cell activation (44), and M-CSF produced by γδ T cells expanded in the livers, lungs, and spleens of Plasmodium chabaudi–infected mice profoundly limited malarial recrudescence (45). However, rather than showing pathogen-specific responses to the complex, Ag-rich microbe, the expanded cells were mostly oligoclonal, innate-like Vγ1Vδ6.3+ cells, which was even more surprising given that Vγ1Vδ6.3+ cells, albeit with slightly different CDR3 sequences, were described among IFN-γ– and IL-4–producing NKT-like γδ cells (46) and among γδ T cells responding during bacterial infections to heat shock protein (hsp) 65–derived peptides mostly conserved from bacteria to mammals (47).

Again, the textbooks do not offer obvious mechanisms explaining the rapid, competitive expansions of oligoclonal, non–microbe-specific γδ T cells and the means by which they contribute to durable host protection. Possibly they manifest “trained immunity,” as exists for nonclonal myeloid cells (48, 49). Potentially consistent with this, murine dermal IL-17–producing γδ T cells rapidly expanded in response to epicutaneous imiquimod (a TLR7 agonist), whereupon they established in nonlesional skin stable compartments of high IL-1R–expressing cells that facilitated greatly enhanced responses to imiquimod re-exposure (50). Clearly, our overall understanding of the complex immune ecologies underpinning tissue immunogenicity can benefit from improved insights into how host responses to rechallenge are promoted in tissues reprogrammed by local, durably altered oligoclonal γδ T cells.

Innate-like responses and butyrophilins.

The response of primate peripheral blood γδ cells to many, albeit not all, microbes is well known and is relevant to sepsis, peritonitis, and other severe pathologies (51). However, rather than being highly specific, the responding cells detect picomolar concentrations of hydroxymethylbut-2-enyl pyrophosphate, an intermediate in sterol metabolism in myriad bacteria, including Mycobacterium tuberculosis, and in plastid-harboring parasites, including Plasmodium. Such moieties are termed “phosphoantigens” (PAgs) because responses are limited to cells expressing particular Vγ9Vδ2 TCRs that can transfer PAg reactivity to heterologous cells. Akin to adaptive immunity, PAg exposure underpins variable postnatal expansions of peripheral blood Vγ9Vδ2 cells (52).

Nonetheless, the limitation of TCR diversity to a single Vγ–Vδ pairing, the cells’ rapid responsiveness, and the widespread occurrence of microbial PAgs collectively evoke innate sensing of pathogen-associated molecular patterns. Indeed, PAg-reactive cells also respond, albeit at higher concentrations, to endogenous sterol intermediates (e.g., isopentenyl pyrophosphate), a molecular pattern commonly upregulated in virus-infected or malignantly transformed cells (53). Over the past several years, it has emerged that PAg responsiveness depends on butyrophilin 3A (BTN3A) proteins (6, 5457), which are poorly understood members of the B7 superfamily of T cell regulators that will now be considered at greater length.

Unlike TCRδ, TCRγ has little potential for diversity (58), a limitation highlighted by Vγ-specific cell expansions during murine T cell development that result in signature tissue-specific γδ T cell compartments, including canonical Vγ5+Vδ1+ dendritic epidermal T cells (DETC), canonical Vγ6+Vδ1+ uterine cells, and oligoclonal Vγ7+ intestinal intraepithelial lymphocytes (IEL). Although humans lack obvious counterparts of DETC, there are skin γδ T cells (59) as well as a major intestinal huVγ4+ IEL compartment (6062) and several other human extralymphoid γδ cell compartments most likely exist. Enrichment at body surfaces might empower γδ cells with rapid surveillance of myriad types of potentially tissue-disruptive challenges. This may be an ancient function under high selective pressure, reflecting which agnathans show enrichment of γδ-equivalent VLR-C+ cells in gut and skin (63); γδ T cell biology may provide a route to understanding this intriguing function.

Associations of defined Vγ elements with discrete tissues suggested that there were tissue-specific, γδTCR-specific selecting ligands, a hypothesis that gained momentum when Vγ5Vδ1+ DETC development was found to depend on Skint1, a Btn-like (Btnl) molecule expressed specifically by thymic epithelial cells and differentiated suprabasal keratinocytes, among which DETC develop and reside, respectively (6467). Likewise, intestinal moVγ7+ IEL development was recently found to depend on Btnl1, largely restricted to intestinal epithelial cells (61, 62).

Btnl proteins most likely exist as heteromers (68), explaining the observation that moVγ7+ IEL downregulated their TCRs and upregulated IL-2Rα (two signatures of TCR engagement) in response to Btnl1 plus Btnl6 but not to either alone (61, 62). Emphasizing evolutionary conservation, human BTNL3 and BTNL8, which are also largely restricted to intestinal epithelial cells, provoked TCR downregulation specifically by huVγ4+ cells, the major colonic TCRγδ+ IEL subtype (61, 62).

The shaping of the skin and gut γδ compartments by Skint1 and Btnl1, respectively, occurred independently of environmental factors (61), suggesting that they comprise bona fide positive-selecting elements akin to CD1d for NKT cells or MHC class I for CD8 T cells. Consistent with this, moVγ7+ and huVγ4+ TCRs, respectively, conferred Btnl1+6-responsiveness and BTNL3+8-responsiveness to heterologous, nonresponsive T cells (62). These responses were largely uninfluenced by TCRδ, being primarily determined by CDR2γ and hypervariable region 4 (HV4), two Vγ subregions closely contiguous in tertiary space (62).

In conclusion, although direct evidence for binding is still lacking, it seems reasonable to consider Btnl/BTNL proteins as γδTCR ligands/Ags, but the T cell response to them is innate by virtue of it being a nonclonotypic property of essentially all TCRs with defined, germline-encoded Vγ–CDR2–HV4 sequences. Clearly, this suggests that polymorphisms in these and possibly other Btnl/BTNL genes contribute to the hereditary selection of TCRVγ genes. The direct impact on Vγ–CDR2–HV4 was in each case mediated by one of the two Btnl/BTNL chains (Btnl6 for moVγ7 and BTNL3 for huVγ4), with the other chains (Btnl1 and BTNL8) seemingly regulating the cellular trafficking and surface expression of the respective heteromers (62, 68).

Clearly, it may be appropriate to evaluate the degree to which this innate modality underpins PAg responses of huVγ9Vδ2 cells, particularly given recent evidence that they depend on a BTN3A1 plus BTN3A2 heteromer (68). Furthermore, recent evidence for a developmental enrichment of PAg-reactive huVγ9Vδ2 cells in utero might reflect intrinsic, BTN3A-dependent selection events akin to those shaping murine DETC and intestinal IEL compartments (16).

Adaptate integration.

Clearly, the three illustrations of γδ T cell expansion need to be better understood. Does each describe a terminally differentiated state, and how do those states compare with one another and with other well-studied states (e.g., adaptive effector/memory αβ T cells, exhausted T cells, or innate-like NKT cells)? Do the durabilities of expanded adaptive γδ clones and of innately expanded tissue-associated compartments share common molecular underpinnings? By comparing and contrasting, we can determine whether γδ T cells bridge innate and adaptive immunity primarily at the population level, comprising qualitatively distinct adaptive and innate cells. That would seem consistent with the division of thymocytes into innate-like and adaptive biologies prior to the γδ/αβ T cell lineage split (69). Conversely, individual γδ T cells might combine innate and adaptive traits in cell-autonomous adaptate biology (Fig. 2).

FIGURE 2.

Mouse and human γδ T cells may bridge innate and adaptive immunity at the population level or at the cell-intrinsic level. (A) Adaptive clonal expansion of γδ T cells driven by signaling from TCR engagement of nominal Ag, regulated by examples of positive (green) and inhibitory (red) costimulation. (B) Innate activation of γδ T cells driven by innate receptor (e.g., NKG2D) engagement of stress ligands, without overt activation of the TCR. (C) Adaptate activation of γδ T cells driven by signaling from TCR engagement of nominal Ag, licensed (narrow arrow) by preceding innate TCR engagement of ligands such as BTNL.

FIGURE 2.

Mouse and human γδ T cells may bridge innate and adaptive immunity at the population level or at the cell-intrinsic level. (A) Adaptive clonal expansion of γδ T cells driven by signaling from TCR engagement of nominal Ag, regulated by examples of positive (green) and inhibitory (red) costimulation. (B) Innate activation of γδ T cells driven by innate receptor (e.g., NKG2D) engagement of stress ligands, without overt activation of the TCR. (C) Adaptate activation of γδ T cells driven by signaling from TCR engagement of nominal Ag, licensed (narrow arrow) by preceding innate TCR engagement of ligands such as BTNL.

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Although huVγ4+ and moVγ7+ cells can be innately regulated by BTNL3 and 8 and Btnl1 and 6, respectively, they can also engage nominal Ags, including human EPCR (see above) and murine MHC-related proteins T10/T22 (35, 70). Nominal Ag responses depend on somatically-recombined CDR3 regions, consistent with their adaptive nature, albeit that gene rearrangement generates the T10/T22-reactive site fairly frequently. Such Ags may drive clonal dominance within repertoires initially selected by innate Vγ-mediated signaling. Neither the mechanism(s) by which tissue-associated γδ T cells sample nominal Ags in situ nor the cells’ antigenic breadth is understood, although there seems to be some enrichment for MHC class I–related proteins (e.g., CD1, EPCR, Qa1, and T10/T22), particularly those upregulated and/or stabilized in dysregulated tissues.

γδ T cells are not intrinsically MHC-restricted. Human γδ T cell infusions induce negligible MHC-dependent graft-versus-host disease (71), and murine γδ cell compartments develop normally in mice lacking β2-microglobulin (β2m; an obligate cofactor for most MHC class I–related molecules) (72). Nonetheless, neither observation excludes the cells’ reacting to nonpolymorphic MHC-related molecules. Moreover, some structural capacity of TCRγδ to complement MHC-related molecules might explain recently described Ab-like TCRγδ reactivities toward melanoma Ag-derived peptides presented by MHC (73).

In sum, adaptate biology may be an evolutionarily conserved trait by which defined γδTCRs can respond to either innate or adaptive ligands via distinct binding modalities. This is not to suggest that both are engaged simultaneously; possibly, innate ligands transduce signals that maintain the cells’ competence to respond to adaptive ligands when the local milieu is dysregulated. Such biology would functionally align BTNL/Btnl proteins with B7 molecules (e.g., B7.1 and/or B7.2 [also known as CD80/CD86]) that inform T cells that an infected context exists, thereby licensing full, TCR-mediated, Ag-specific effector responses. This is the founding paradigm bridging innate with adaptive immunity (74).

Functional alignment of BTNL/Btnl proteins is paralleled by structural alignment, with nuclear magnetic resonance–based data showing the Skint1 ectodomain to be strikingly similar to PDL1 (75), a B7-like molecule that communicates to T cells a state of heightened immune activation, thereupon dampening TCR-mediated responsiveness. The possibility that Skint/Btnl/BTNL proteins communicate tissue status to local T cells is fueled by the restriction of their expression to postmitotic differentiated epithelial cells. In short, γδ T cells engaging Skint/Btnl/BTNL would know 1) where they were (skin/gut) and 2) the status of the tissue (homeostatic “normality”). Thereby, local γδ T cells may be uniquely well placed for tissue sensing.

The tightly regulated expression of Btnl/BTNL might be sufficient to define normality. Alternatively, the proteins may phenocopy BTN3A1, whose intracellular B30.2 domain binds PAgs (56), the concentrations of which are upregulated by cell infection and/or dysregulation and which can, therefore, be classified as danger-associated molecular patterns (DAMPs). Upon B30.2 binding, BTN3A1 is conformationally altered, purportedly promoting TCR triggering (56, 76), albeit by unknown mechanisms. Thus, there is an intriguing potential for BTNL B30.2 domains to likewise act as intracellular status sensors, and although Skint1 lacks a B30.2 domain, it includes multiple transmembrane-pass regions that may also sense cellular normality. By whichever means, Btnl/BTNL/Skint gene products may fulfill the roles of DAMP-sensing B7 molecules, communicating the status of the tissue to preselected sets of local T cells.

Tissue sensing by local T cells may be manifest in observations of murine gut γδ IEL dynamically engaging the basolateral sides of enterocytes (7779). Although somewhat different observations were reported, the aggregate findings were that, following gut infection, particularly by attaching–effacing bacteria, enterocytes could provoke γδ IEL to increase their ATP utilization, facilitating their accelerated mobility up and down the villi (79). The regulators of mobility included occludin, CD103, the glucose transporter Glut1, and IL-15, and reduced mobility was associated with increased transepithelial invasiveness of S. typhimurium or Toxoplasma gondii (78, 79). For Vγ5Vδ1+ DETC, tissue sensing is seemingly manifest in TCR-rich clusters that appose neighboring keratinocytes at steady state but which are disrupted upon epithelial dysregulation as a preface to full T cell activation (80) again evoking licensing.

The perception via the TCR of both tissue status and nominal Ags may require that innate and adaptive ligands transduce distinct intracellular signals. As precedent, the profound effects of microbial and/or endogenous superantigens on αβ T cells are primarily mediated by TCRβ–HV4, which transduces signals distinct from those transduced by CDRs engaging peptide–MHC (81). Indeed, innate tissue sensing may transduce signals akin to tonic signaling or chronic Ag stimulation. In this regard, Skint/Btnl-selected γδ T cells are rich in Nr4a transcriptional regulators, which compose signatures of chronically activated CD8+ TCRαβ+ tumor-infiltrating lymphocytes (82). However, whereas Nr4a+ tumor-infiltrating lymphocytes are commonly regarded as exhausted, tissue-associated Nr4a+ γδ T cells are better considered as activated-yet-resting (83), sustaining cellular competence to respond to nominal Ags.

Tissue status may also be sensed by NKG2D, an activating receptor widely expressed by NK cells, CD8+ αβ T cells, and tissue-resident γδ T cells. NKG2D ligands Rae-1 (mouse) or MICA/ULBP (human) are strong candidates for DAMPs in human carcinoma because they are upregulated by DNA damage and by hyperactive epithelial growth factor receptor signaling (84, 85). Consistent with this biology, NKG2D is a coreceptor for TCR signaling on CD8+ αβ T cells (86). By contrast, DETC responded rapidly in vivo to acute local Rae-1ε upregulation without overt TCR stimulation, arguing for the cells’ classification as innate T cells (87, 88). Moreover, Rae-1ε–induced DETC activation initiated several downstream immunological events akin to those initiated by innately activated myeloid cells (87, 88).

However, were the Vγ5Vδ1+ DETC TCR to be constitutively engaged (e.g., by Skint1), the DETC may not have been responding only to innate NKG2D ligands. Likewise, innate TCR activation may license target recognition by other innate receptors such as NKp30 (89) or WC1, an antimicrobial scavenger receptor expressed by a major subset of bovine γδ T cells (90, 91) (Fig. 2). In fact, prior Skint1-mediated selection is required to transform Vγ5Vδ1+ DETC progenitors into T cells strongly responsive to innate receptor engagement but with relatively attenuated responsiveness to conventional TCR stimulation (92). Upon Skint1/Btnl1-mediated selection, DETC and IEL upregulate CD45RB, and when hitherto uncharacterized CD45RBhi γδ cells were purified from lymphoid organs, they, too, combined atypical TCR responsiveness with strong innate responses (92), an integrated state reinforcing an adaptate view of γδ T cells.

This is not to suggest that TCR-mediated innate sensing is a unique means of tissue and/or context sensing by γδ T cells, because they express several other significant receptors, including Gpr55, JAML, CD100, 4-1BB, and the aryl hydrocarbon receptor (61, 9396) (Fig. 2), that may make the cells particularly adept at homing to, residing within, and then discriminating the status of tissues. Likewise, γδ T cells may be inhibited by TIGIT and/or other negative regulators (Fig. 2). Importantly, expression of different receptors should facilitate receipt of different information flows from many different cell types that tissue- and tumor-resident γδ cells interact with.

Functional preprogramming.

Another consequence of γδ T cell selection is effector skewing. Skint1-mediated selection suppressed Sox13 and Rorc expression, skewing DETC progenitors away from IL-17 production, which is likewise suppressed in Btnl1-selected Vγ7+ IEL and in T10/T22-specific γδ cells that engage their ligand during development (61, 67, 97). Likewise, TCR signals are required for murine Vδ6.3+ cells to skew toward either IL-4 or IFN-γ production (98).

Developmental preprogramming is not universal, as PE-reactive γδ T cells (above) were skewed toward IL-17 in the periphery following Ag priming of functionally uncommitted cells, seemingly consistent with the adaptive biology of conventional αβ T cells (40, 99). Nonetheless, its broad significance was established when a large faction of mouse TCRγδ+ thymocytes expressing CD27 and CD122 was found to be IFN-γ–skewed, with CD27 acting as a coreceptor, enabling the immature cells to survive strong TCR-mediated signals (100, 101). Indeed, IL-17 expression became epigenetically excluded in CD27+ cells (102). Conversely, murine CD44hiCCR6+CD122loCD27 thymocytes preprogrammed toward IL-17 (100) are progenitors of several well studied, potently proinflammatory murine γδ cell compartments that respond rapidly to innate stimuli, particularly IL-1 and IL-231 (14, 15, 21, 103105). Furthermore, the functional biases of CD27+ and CD27 cells, respectively, were amplified during their expansions in P. berghei–infected mice (101).

Functional skewing can show striking microanatomical segregation, with IL-17 produced by subepithelial compartments (e.g., dermal and LP γδ T cells) but seemingly excluded from healthy epithelium. Note that, although DETC and IEL are IFN-γ−biased, their IFN-γ production is often minimal, suggesting that other effectors better describe their host benefit. Likewise, although most γδ subsets have high cytolytic potential, where and when such activity is ordinarily deployed is unclear. Better understanding of the microanatomical segregation of γδ T cell functions could provide useful insight into how local lymphocytes are integrated with loco-regional physiology at steady state and during tissue inflammation.

Selected or default? Related or distinct?

As first noted by Born and O'Brien (105), function also segregates to some extent with TCR usage: CD27+ IFN-γ producers are primarily Vγ1+, whereas CD27 IL-17 producers mostly express Vγ4 or limited-diversity Vγ6 TCRs, including those showing quasi-adaptive expansion in L. monocytogenes infection. These observations suggest that the γδ17 phenotype can also be preprogrammed by TCRVγ-selective activation; consistent with this, γδ17 progenitors are CD44hi, show strikingly attenuated TCR responsiveness (100), and are disproportionately depleted in Skg mice, in which the function of the TCR-proximal signaling kinase Zap70 is reduced by ∼90% (92). Likewise, Vγ6+ IL-17 producers are essentially ablated by haploinsufficiency of both CD3 γ- and CD3 δ-chain genes (106). The cells’ innate-like activity is also suggested by their limited expression of genes encoding TCR signaling components (107).

Nonetheless, TCRVγ-specific selection is not yet established for IL-17–producing γδ T cells, and the possibility exists that they are a default state suppressed by ligand-dependent γδ selection (67, 97). Indeed, γδ17 progenitors are reportedly intolerant of strong TCRγδ signaling (108), despite the fact that strong TCR-mediated signals are seemingly required for early T cell progenitors to become γδ versus αβ T cells (109, 110).

Possibly, strength-of-signal is less significant than qualitatively distinct signals [e.g., differences in ERK activity (110)] that might reflect different TCR signaling modalities, for example, via CDR2–HV4 (62) or via ligand-independent dimerization (97), as is considered for pre–TCR signaling in αβ T cell development. Possibly, SLAM–SAP signaling in vivo permits γδ17 progenitors to survive strong TCR signals, as was recently shown for invariant NKT cell development (111). Clearly, the identification of physiologic ligands, particularly for canonical Vγ6+ T cells, should resolve this and other aspects of γδ17 biology. The same would be true for oligoclonal Vγ1Vδ6.3+ cells, whose TCR is critical for their adopting a defining NKT-like phenotype (98).

At the same time, TCR signals might be altered by context (e.g., coincident signals via Notch, cytokines, and/or other cell surface regulators, and regulation by microRNAs) (112115). Recently, the transcription factor c-maf was shown to promote the developmental acquisition of the γδ17 phenotype, in part by promoting Rorgt activity and by suppressing Tcf7, whose gene product, Tcf1, promotes the γδIFN-γ phenotype (116). This may parallel the c-maf–driven switch of TCRαβ+ T regulatory (Treg) cells into IL-17 producers. Likewise, γδ17 differentiation is promoted by the transcription factor PLZF, which is generally associated with innate-like T cell phenotypes (117) and is specifically required for NKT-like γδ cells (98).

Such signature gene regulatory networks might also suggest that IFN-γ–skewed and IL-17–skewed γδ T cells arise independently from qualitatively distinct progenitors (118). This could relate to the limited and unique developmental windows during which distinct γδ T cells emerge and to the report that γδ17 cells arise from type 3 innate lymphoid cell (ILC)-like IL-17–producing thymocytes (14). This perspective would be consistent with there being many other differences between IFN-γ–skewed and IL-17–skewed γδ T cells. For example, the latter harbor low levels glutathione, making them susceptible to reactive oxygen species produced by neutrophils (119). This may reflect γδ subset–specific negative feedback regulation required to protect tissues. For example, in response to the commensal Corynebacterium mastitidis, ocular γδ17 cells recruit neutrophils, which release antimicrobials into tears that protect the eye from pathogenic fungi and bacteria but that, in excess, could cause immunopathologic conditions (120).

Complexities and controversies.

An increasing sophistication of phenotyping has begun to reveal that γδ T cells are relevant to very many aspects of pathophysiologic conditions. For example, murine PLZF+ Vγ6+ cells resident in adipose tissue produce IL-17A and TNF, which, by regulating IL-33 production by stromal cells, indirectly maintain local type 2 ILC and Treg cells that jointly regulate adipose tissue homeostasis (121). Additionally, γδ T cell–derived IL-17A and TNF directly stimulated expression of uncoupling protein 1 in adipocytes, favoring thermogenesis. As a result, TCRδ−/− mice displayed low body temperature and increased breathing at thermoneutrality and particularly after cold challenge (121).

The inference of γδ T cell function from TCRδ−/− mice is inevitably somewhat qualified by developmental adaptations to γδ cell deficiency, including ectopic potentials of replacement αβ T cell and ILC repertoires. The recent development of mice with conditional γδ T cell deficiency (122) has reduced this uncertainty, confirming that misdirection of antimicrobial potentials of dermal γδ17 cells underpins imiquimod-induced psoriasis, a phenotype that a high-fat diet exacerbates by increasing γδ17 cell numbers (122).

The thin line between tissue regulation and immunopathologic conditions is also illustrated by the relationship of γδ17 cells and commensals. IL-17 secreted by lung Vγ6Vδ1+ cells responding to IL-1 and IL-23 produced by commensal-sensing myeloid cells may beneficially regulate local host–microbe interactions, akin to the induction by skin commensals of nonclassical MHC class I–restricted CD8 T cells that effected tissue regulation (123). However, IL-17 produced by Vγ6Vδ1+ cells indirectly responding to commensals in the same way drove neutrophil activation that promoted lung cancers in a transgenic “p53-loss, activated Kras” mouse model (124). Similarly, a γδ/IL-17/neutrophil axis promoted lung and LN metastasis in a murine breast cancer model (26), in part via CD8 T cell immunosuppression. IL-17 may also promote carcinomas via direct effects on epithelial cells. In addition to this, γδ17 cells may exacerbate inflammation by changing from CCR6-based homing into steady-state compartments to CCR2-dependent migration to inflammatory lesional sites (125).

Nonetheless, at least two levels of complexity provide important contexts for these studies. First, γδ17 cells can also produce IL-22, which promotes antimicrobial peptide production and epithelial repair, which can suppress inflammation and carcinogenesis (126). Indeed, retinoic acid reduces inflammation induced by either Citrobacter infection or dextran sodium sulfate by promoting γδ T cell–dependent IL-22 upregulation (126).

Likewise, although gingival γδ T cells can produce IL-17, a potential mediator of periodontal inflammation, their aggregate role following oral surface damage was to produce amphiregulin, which promoted barrier repair and the reestablishment of homeostasis (127). Likewise, IL-17 produced by murine γδ T cells responding to neonatal influenza infection promoted IL-33 production by lung epithelial cells (128). IL-33, in turn, promoted lung infiltration of type 2 ILC and Treg cells that produced amphiregulin, which critically contributed to tissue repair. Furthermore, IL-17A, IL-33, and amphiregulin expression were correlated in influenza-infected children, although a direct linkage to γδ T cells was not shown (128). In short, it is inappropriate to assume either that IL-17 is the primary effector of γδ17 cells or that the key pathophysiologic impact of γδ17 cells is proinflammatory, and one should be cautious in interpreting experimental systems that may exaggerate that phenotype.

Second, there is strikingly little evidence for human γδ17 cells that were either preprogrammed or differentiated de novo in the periphery. Possibly, human γδ17 cells are obscure because they sit within tissues, occupy discrete ontogenetic windows, or are associated with specific pathological conditions. Indeed, rare examples of their detection in colorectal cancer and in human papillomavirus–rich vulval lesions were associated with cancer promotion (24, 25). Nonetheless, efforts to generate and/or expand human γδ17 cells have proved conspicuously challenging (129).

This potentially major difference between human and mouse γδ biologies might be because CXCL8 (whose gene is missing from the mouse genome) can replace γδ-derived IL-17 in regulating neutrophils. Possibly, the developmental pathway skewed toward γδ17 cells is less significant in humans, just as mice lack overt counterparts of PAg-reactive Vγ9Vδ2+ cells. Indeed, species-specific differences are highlighted in the potent capacity of huVγ9Vδ2+ cells to present Ag to T cells. Because such activity is not obviously conserved in mice, it has been somewhat understudied, with its physiologic context(s) unresolved. Recently, however, it was shown that blood and intestinal Vγ9Vδ2+ cells that acquired Ag-presenting functions upon microbial activation in the presence of IL-15 could skew responding TCRαβ CD4+ T cells toward IL-22 without upregulating IL-17 (130). Such selective skewing has not been shown for myeloid APCs and may reflect an additional unique contribution of γδ T cells to tissue surveillance.

In sum, the aggregate outcome(s) of γδ T cell activation can be highly case-specific and species-specific and will only be understood by better characterizing the multicomponent immune ecologies of specific responses to defined challenges. Although most human γδ T cell subsets display cytolytic IFN-γ–skewing akin to murine IEL and CD27+ lymphoid γδ T cells, it is possible that pathologic reprogramming can redirect them toward IL-17 production in inflammation and/or cancer. In this vein, pathologic dysregulation of the intestinal huVγ4+–BTNL3 axis was recently reported to contribute to the potent inflammatory milieu in celiac disease, for which intestinal γδ T cell expansion is a pathognomonic feature (131).

In the clinic.

There are growing efforts to develop γδ T cells as immunotherapeutics in cancer. In contrast to the implication of γδ17 cells in promoting inflammation-associated cancer, a wealth of diverse studies underscore host-beneficial effects of γδ T cells in mice and humans (71, 87, 132135). This seems consistent with the cells’ potential to home to and operate in the hypoxic conditions commonplace in solid tumors; their adaptate capacity to sense tissue status and thereby to discriminate between normal and dysregulated cells; their cytolytic IFN-γ bias; their immunogenic capacity to promote other immune cell activities, including by Ag presentation; and their relative insensitivity to PD1- or Treg-mediated inhibition.

Moreover, ongoing investigations of γδ T cells are casting new light onto cancer immunosurveillance. For example, activated DETC can rapidly produce IL-13, which can both promote type 2 B cell responses and promote epithelial repair (136). This intriguing link of γδ T cell–mediated lymphoid stress surveillance to atopy (88) may permit IgE to neutralize carcinogens and other toxins while tissue repair occurs. Indeed, an FcεR1-dependent IgE response driven by DETC responding to epicutaneous dimethylbenzanthracene (a dioxin-like carcinogen) protected mice against carcinogenesis, and FcεRI gene expression positively correlated with disease outcome in human squamous cell carcinoma (137). In practical terms, the recogntion of tissue dysregulation and the lack of MHC restriction of γδ T cells and other unconventional T cells have three potentially profound implications: their recognition of tumors will not be limited to those with high mutational loads required to generate peptide neoantigens; they will be unaffected by MHC loss-mediated immune evasion; and they may be efficacious in allogeneic recipients, thereby opening a door to off-the-shelf therapies.

In sum, many unique features of γδ T cells continue to emerge, including, but not limited to, their adaptate biology. Those features permit them to contribute to host protection in unprecedented ways, and their continued investigation promises to provide new and important insights into how tissue immunogenicity is balanced against the need to avoid inflammatory pathological conditions, and the complex interactions between multiple immune cells that will collectively compose tissue-specific immune ecologies. In this regard, understanding the specificities of adaptive γδ T cells will be essential to understanding the pressures that have presumably maintained evolutionary selection on the capacity to generate diverse Ag receptors in three distinct cell lineages. Likewise, a greater understanding of the cells' biology may refine and optimize the clinical application of these natural orchestrators of immune surveillance.

I dedicate this review to Drs. W. Born and R. Tigelaar, who have each announced retirement after contributing monumentally to this field. I apologize to those whose work was not mentioned, largely because of space constraints, and particularly where I have opted to cite recent reviews. I thank many colleagues and members of the laboratory for stimulating discussions and clarifications and Ralph Budd (University of Vermont) for permitting me to cite unpublished work. I am grateful for funding from a Wellcome Trust Senior Investigator Award and the Francis Crick Institute.

This work was supported by the Wellcome Trust and the Francis Crick Institute.

Abbreviations used in this article:

     
  • BTN3A

    butyrophilin 3A

  •  
  • Btnl

    Btn-like

  •  
  • DAMP

    danger-associated molecular pattern

  •  
  • DETC

    dendritic epidermal T cell

  •  
  • EPCR

    epithelial protein C receptor

  •  
  • HV4

    hypervariable region 4

  •  
  • IEL

    intraepithelial lymphocyte

  •  
  • ILC

    innate lymphoid cell

  •  
  • LN

    lymph node

  •  
  • LP

    lamina propria

  •  
  • PAg

    phosphoantigen

  •  
  • Treg

    T regulatory.

1
Hayday
,
A. C.
,
H.
Saito
,
S. D.
Gillies
,
D. M.
Kranz
,
G.
Tanigawa
,
H. N.
Eisen
,
S.
Tonegawa
.
1985
.
Structure, organization, and somatic rearrangement of T cell gamma genes.
Cell
40
:
259
269
.
2
Kasamatsu
,
J.
,
Y.
Sutoh
,
K.
Fugo
,
N.
Otsuka
,
K.
Iwabuchi
,
M.
Kasahara
.
2010
.
Identification of a third variable lymphocyte receptor in the lamprey.
Proc. Natl. Acad. Sci. USA
107
:
14304
14308
.
3
Boismenu
,
R.
,
W. L.
Havran
.
1994
.
Modulation of epithelial cell growth by intraepithelial gamma delta T cells.
Science
266
:
1253
1255
.
4
Vidović
,
D.
,
M.
Roglić
,
K.
McKune
,
S.
Guerder
,
C.
MacKay
,
Z.
Dembić
.
1989
.
Qa-1 restricted recognition of foreign antigen by a gamma delta T-cell hybridoma.
Nature
340
:
646
650
.
5
Vantourout
,
P.
,
A.
Hayday
.
2013
.
Six-of-the-best: unique contributions of γδ T cells to immunology.
Nat. Rev. Immunol.
13
:
88
100
.
6
Willcox
,
B. E.
,
C. R.
Willcox
.
2019
.
γδ TCR ligands: the quest to solve a 500-million-year-old mystery. [Published erratum appears in 2019 Nat. Immunol. 20: 516.]
Nat. Immunol.
20
:
121
128
.
7
Rock
,
E. P.
,
P. R.
Sibbald
,
M. M.
Davis
,
Y. H.
Chien
.
1994
.
CDR3 length in antigen-specific immune receptors.
J. Exp. Med.
179
:
323
328
.
8
Parra
,
Z. E.
,
Y.
Ohta
,
M. F.
Criscitiello
,
M. F.
Flajnik
,
R. D.
Miller
.
2010
.
The dynamic TCRδ: TCRδ chains in the amphibian Xenopus tropicalis utilize antibody-like V genes.
Eur. J. Immunol.
40
:
2319
2329
.
9
Parra
,
Z. E.
,
M. L.
Baker
,
R. S.
Schwarz
,
J. E.
Deakin
,
K.
Lindblad-Toh
,
R. D.
Miller
.
2007
.
A unique T cell receptor discovered in marsupials.
Proc. Natl. Acad. Sci. USA
104
:
9776
9781
.
10
Criscitiello
,
M. F.
,
M.
Saltis
,
M. F.
Flajnik
.
2006
.
An evolutionarily mobile antigen receptor variable region gene: doubly rearranging NAR-TcR genes in sharks.
Proc. Natl. Acad. Sci. USA
103
:
5036
5041
.
11
Hayday
,
A. C.
2000
.
[gamma][delta] cells: a right time and a right place for a conserved third way of protection.
Annu. Rev. Immunol.
18
:
975
1026
.
12
Parra
,
Z. E.
,
M. L.
Baker
,
A. M.
Lopez
,
J.
Trujillo
,
J. M.
Volpe
,
R. D.
Miller
.
2009
.
TCR mu recombination and transcription relative to the conventional TCR during postnatal development in opossums.
J. Immunol.
182
:
154
163
.
13
Havran
,
W. L.
,
J. P.
Allison
.
1990
.
Origin of Thy-1+ dendritic epidermal cells of adult mice from fetal thymic precursors.
Nature
344
:
68
70
.
14
Haas
,
J. D.
,
S.
Ravens
,
S.
Düber
,
I.
Sandrock
,
L.
Oberdörfer
,
E.
Kashani
,
V.
Chennupati
,
L.
Föhse
,
R.
Naumann
,
S.
Weiss
, et al
.
2012
.
Development of interleukin-17-producing γδ T cells is restricted to a functional embryonic wave.
Immunity
37
:
48
59
.
15
Shibata
,
K.
,
H.
Yamada
,
M.
Nakamura
,
S.
Hatano
,
Y.
Katsuragi
,
R.
Kominami
,
Y.
Yoshikai
.
2014
.
IFN-γ-producing and IL-17-producing γδ T cells differentiate at distinct developmental stages in murine fetal thymus.
J. Immunol.
192
:
2210
2218
.
16
Dimova
,
T.
,
M.
Brouwer
,
F.
Gosselin
,
J.
Tassignon
,
O.
Leo
,
C.
Donner
,
A.
Marchant
,
D.
Vermijlen
.
2015
.
Effector Vγ9Vδ2 T cells dominate the human fetal γδ T-cell repertoire.
Proc. Natl. Acad. Sci. USA
112
:
E556
E565
.
17
Ramsburg
,
E.
,
R.
Tigelaar
,
J.
Craft
,
A.
Hayday
.
2003
.
Age-dependent requirement for gammadelta T cells in the primary but not secondary protective immune response against an intestinal parasite.
J. Exp. Med.
198
:
1403
1414
.
18
Gibbons
,
D. L.
,
S. F.
Haque
,
T.
Silberzahn
,
K.
Hamilton
,
C.
Langford
,
P.
Ellis
,
R.
Carr
,
A. C.
Hayday
.
2009
.
Neonates harbour highly active gammadelta T cells with selective impairments in preterm infants.
Eur. J. Immunol.
39
:
1794
1806
.
19
Hayday
,
A. C.
2009
.
Gammadelta T cells and the lymphoid stress-surveillance response.
Immunity
31
:
184
196
.
20
Jameson
,
J.
,
K.
Ugarte
,
N.
Chen
,
P.
Yachi
,
E.
Fuchs
,
R.
Boismenu
,
W. L.
Havran
.
2002
.
A role for skin gammadelta T cells in wound repair.
Science
296
:
747
749
.
21
Sutton
,
C. E.
,
S. J.
Lalor
,
C. M.
Sweeney
,
C. F.
Brereton
,
E. C.
Lavelle
,
K. H.
Mills
.
2009
.
Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity.
Immunity
31
:
331
341
.
22
Markle
,
J. G.
,
S.
Mortin-Toth
,
A. S.
Wong
,
L.
Geng
,
A.
Hayday
,
J. S.
Danska
.
2013
.
γδ T cells are essential effectors of type 1 diabetes in the nonobese diabetic mouse model.
J. Immunol.
190
:
5392
5401
.
23
Cai
,
Y.
,
X.
Shen
,
C.
Ding
,
C.
Qi
,
K.
Li
,
X.
Li
,
V. R.
Jala
,
H. G.
Zhang
,
T.
Wang
,
J.
Zheng
,
J.
Yan
.
2011
.
Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation.
Immunity
35
:
596
610
.
24
Wu
,
P.
,
D.
Wu
,
C.
Ni
,
J.
Ye
,
W.
Chen
,
G.
Hu
,
Z.
Wang
,
C.
Wang
,
Z.
Zhang
,
W.
Xia
, et al
.
2014
.
γδT17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer.
Immunity
40
:
785
800
.
25
Van Hede
,
D.
,
B.
Polese
,
C.
Humblet
,
A.
Wilharm
,
V.
Renoux
,
E.
Dortu
,
L.
de Leval
,
P.
Delvenne
,
C. J.
Desmet
,
F.
Bureau
, et al
.
2017
.
Human papillomavirus oncoproteins induce a reorganization of epithelial-associated γδ T cells promoting tumor formation.
Proc. Natl. Acad. Sci. USA
114
:
E9056
E9065
.
26
Coffelt
,
S. B.
,
K.
Kersten
,
C. W.
Doornebal
,
J.
Weiden
,
K.
Vrijland
,
C. S.
Hau
,
N. J. M.
Verstegen
,
M.
Ciampricotti
,
L. J. A. C.
Hawinkels
,
J.
Jonkers
,
K. E.
de Visser
.
2015
.
IL-17-producing γδ T cells and neutrophils conspire to promote breast cancer metastasis.
Nature
522
:
345
348
.
27
Davey
,
M. S.
,
C. R.
Willcox
,
S. P.
Joyce
,
K.
Ladell
,
S. A.
Kasatskaya
,
J. E.
McLaren
,
S.
Hunter
,
M.
Salim
,
F.
Mohammed
,
D. A.
Price
, et al
.
2017
.
Clonal selection in the human Vδ1 T cell repertoire indicates γδ TCR-dependent adaptive immune surveillance.
Nat. Commun.
8
:
14760
.
28
Davey
,
M. S.
,
C. R.
Willcox
,
S.
Hunter
,
S. A.
Kasatskaya
,
E. B. M.
Remmerswaal
,
M.
Salim
,
F.
Mohammed
,
F. J.
Bemelman
,
D. M.
Chudakov
,
Y. H.
Oo
,
B. E.
Willcox
.
2018
.
The human Vδ2+ T-cell compartment comprises distinct innate-like Vγ9+ and adaptive Vγ9- subsets.
Nat. Commun.
9
:
1760
.
29
Hunter
,
S.
,
C. R.
Willcox
,
M. S.
Davey
,
S. A.
Kasatskaya
,
H. C.
Jeffery
,
D. M.
Chudakov
,
Y. H.
Oo
,
B. E.
Willcox
.
2018
.
Human liver infiltrating γδ T cells are composed of clonally expanded circulating and tissue-resident populations.
J. Hepatol.
69
:
654
665
.
30
Ravens
,
S.
,
C.
Schultze-Florey
,
S.
Raha
,
I.
Sandrock
,
M.
Drenker
,
L.
Oberdörfer
,
A.
Reinhardt
,
I.
Ravens
,
M.
Beck
,
R.
Geffers
, et al
.
2017
.
Human γδ T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection. [Published erratum appears in 2018 Nat. Immunol. 19: 1037.]
Nat. Immunol.
18
:
393
401
.
31
Vermijlen
,
D.
,
M.
Brouwer
,
C.
Donner
,
C.
Liesnard
,
M.
Tackoen
,
M.
Van Rysselberge
,
N.
Twité
,
M.
Goldman
,
A.
Marchant
,
F.
Willems
.
2010
.
Human cytomegalovirus elicits fetal gammadelta T cell responses in utero.
J. Exp. Med.
207
:
807
821
.
32
Khairallah
,
C.
,
S.
Netzer
,
A.
Villacreces
,
M.
Juzan
,
B.
Rousseau
,
S.
Dulanto
,
A.
Giese
,
P.
Costet
,
V.
Praloran
,
J. F.
Moreau
, et al
.
2015
.
γδ T cells confer protection against murine cytomegalovirus (MCMV).
PLoS Pathog.
11
: e1004702.
33
Devaud
,
C.
,
E.
Bilhere
,
S.
Loizon
,
V.
Pitard
,
C.
Behr
,
J. F.
Moreau
,
J.
Dechanet-Merville
,
M.
Capone
.
2009
.
Antitumor activity of gammadelta T cells reactive against cytomegalovirus-infected cells in a mouse xenograft tumor model.
Cancer Res.
69
:
3971
3978
.
34
Couzi
,
L.
,
Y.
Levaillant
,
A.
Jamai
,
V.
Pitard
,
R.
Lassalle
,
K.
Martin
,
I.
Garrigue
,
O.
Hawchar
,
F.
Siberchicot
,
N.
Moore
, et al
.
2010
.
Cytomegalovirus-induced gammadelta T cells associate with reduced cancer risk after kidney transplantation.
J. Am. Soc. Nephrol.
21
:
181
188
.
35
Willcox
,
C. R.
,
V.
Pitard
,
S.
Netzer
,
L.
Couzi
,
M.
Salim
,
T.
Silberzahn
,
J. F.
Moreau
,
A. C.
Hayday
,
B. E.
Willcox
,
J.
Déchanet-Merville
.
2012
.
Cytomegalovirus and tumor stress surveillance by binding of a human γδ T cell antigen receptor to endothelial protein C receptor.
Nat. Immunol.
13
:
872
879
.
36
Marlin
,
R.
,
A.
Pappalardo
,
H.
Kaminski
,
C. R.
Willcox
,
V.
Pitard
,
S.
Netzer
,
C.
Khairallah
,
A. M.
Lomenech
,
C.
Harly
,
M.
Bonneville
, et al
.
2017
.
Sensing of cell stress by human γδ TCR-dependent recognition of annexin A2.
Proc. Natl. Acad. Sci. USA
114
:
3163
3168
.
37
Shi
,
C.
,
B.
Sahay
,
J. Q.
Russell
,
K. A.
Fortner
,
N.
Hardin
,
T. J.
Sellati
,
R. C.
Budd
.
2011
.
Reduced immune response to Borrelia burgdorferi in the absence of γδ T cells.
Infect. Immun.
79
:
3940
3946
.
38
Collins
,
C.
,
C.
Shi
,
J. Q.
Russell
,
K. A.
Fortner
,
R. C.
Budd
.
2008
.
Activation of gamma delta T cells by Borrelia burgdorferi is indirect via a TLR- and caspase-dependent pathway.
J. Immunol.
181
:
2392
2398
.
39
Hogg
,
A. E.
,
A.
Worth
,
P.
Beverley
,
C. J.
Howard
,
B.
Villarreal-Ramos
.
2009
.
The antigen-specific memory CD8+ T-cell response induced by BCG in cattle resides in the CD8+gamma/deltaTCR-CD45RO+ T-cell population.
Vaccine
27
:
270
279
.
40
Zeng
,
X.
,
Y. L.
Wei
,
J.
Huang
,
E. W.
Newell
,
H.
Yu
,
B. A.
Kidd
,
M. S.
Kuhns
,
R. W.
Waters
,
M. M.
Davis
,
C. T.
Weaver
,
Y. H.
Chien
.
2012
.
γδ T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response.
Immunity
37
:
524
534
.
41
Baldwin
,
C. L.
,
J. C.
Telfer
.
2015
.
The bovine model for elucidating the role of γδ T cells in controlling infectious diseases of importance to cattle and humans.
Mol. Immunol.
66
:
35
47
.
42
Sheridan
,
B. S.
,
P. A.
Romagnoli
,
Q. M.
Pham
,
H. H.
Fu
,
F.
Alonzo
III
,
W. D.
Schubert
,
N. E.
Freitag
,
L.
Lefrançois
.
2013
.
γδ T cells exhibit multifunctional and protective memory in intestinal tissues.
Immunity
39
:
184
195
.
43
Simonian
,
P. L.
,
C. L.
Roark
,
F.
Wehrmann
,
A. K.
Lanham
,
F.
Diaz del Valle
,
W. K.
Born
,
R. L.
O’Brien
,
A. P.
Fontenot
.
2009
Th17-polarized immune response in a murine model of hypersensitivity pneumonitis and lung fibrosis
.
J. Immunol.
182
:
657
665
.
44
Seder
,
R. A.
,
L. J.
Chang
,
M. E.
Enama
,
K. L.
Zephir
,
U. N.
Sarwar
,
I. J.
Gordon
,
L. A.
Holman
,
E. R.
James
,
P. F.
Billingsley
,
A.
Gunasekera
, et al
VRC 312 Study Team
.
2013
.
Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine.
Science
341
:
1359
1365
.
45
Mamedov
,
M. R.
,
A.
Scholzen
,
R. V.
Nair
,
K.
Cumnock
,
J. A.
Kenkel
,
J. H. M.
Oliveira
,
D. L.
Trujillo
,
N.
Saligrama
,
Y.
Zhang
,
F.
Rubelt
, et al
.
2018
.
A macrophage colony-stimulating-factor-producing γδ T Cell subset prevents malarial parasitemic recurrence.
Immunity
48
:
350
363.e7
.
46
Gerber
,
D. J.
,
V.
Azuara
,
J. P.
Levraud
,
S. Y.
Huang
,
M. P.
Lembezat
,
P.
Pereira
.
1999
.
IL-4-producing gamma delta T cells that express a very restricted TCR repertoire are preferentially localized in liver and spleen.
J. Immunol.
163
:
3076
3082
.
47
Born
,
W.
,
L.
Hall
,
A.
Dallas
,
J.
Boymel
,
T.
Shinnick
,
D.
Young
,
P.
Brennan
,
R.
O’Brien
.
1990
.
Recognition of a peptide antigen by heat shock--reactive gamma delta T lymphocytes.
Science
249
:
67
69
.
48
Bekkering
,
S.
,
R. J. W.
Arts
,
B.
Novakovic
,
I.
Kourtzelis
,
C. D. C. C.
van der Heijden
,
Y.
Li
,
C. D.
Popa
,
R.
Ter Horst
,
J.
van Tuijl
,
R. T.
Netea-Maier
, et al
.
2018
.
Metabolic induction of trained immunity through the mevalonate pathway.
Cell
172
:
135
146.e9
.
49
Moorlag
,
S. J. C. F. M.
,
R. J.
Röring
,
L. A. B.
Joosten
,
M. G.
Netea
.
2018
.
The role of the interleukin-1 family in trained immunity.
Immunol. Rev.
281
:
28
39
.
50
Ramírez-Valle
,
F.
,
E. E.
Gray
,
J. G.
Cyster
.
2015
.
Inflammation induces dermal Vγ4+ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17-driven responses.
Proc. Natl. Acad. Sci. USA
112
:
8046
8051
.
51
Davey
,
M. S.
,
C. Y.
Lin
,
G. W.
Roberts
,
S.
Heuston
,
A. C.
Brown
,
J. A.
Chess
,
M. A.
Toleman
,
C. G.
Gahan
,
C.
Hill
,
T.
Parish
, et al
.
2011
.
Human neutrophil clearance of bacterial pathogens triggers anti-microbial γδ T cell responses in early infection.
PLoS Pathog.
7
: e1002040.
52
Parker
,
C. M.
,
V.
Groh
,
H.
Band
,
S. A.
Porcelli
,
C.
Morita
,
M.
Fabbi
,
D.
Glass
,
J. L.
Strominger
,
M. B.
Brenner
.
1990
.
Evidence for extrathymic changes in the T cell receptor gamma/delta repertoire.
J. Exp. Med.
171
:
1597
1612
.
53
Gober
,
H. J.
,
M.
Kistowska
,
L.
Angman
,
P.
Jenö
,
L.
Mori
,
G.
De Libero
.
2003
.
Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells.
J. Exp. Med.
197
:
163
168
.
54
Harly
,
C.
,
Y.
Guillaume
,
S.
Nedellec
,
C. M.
Peigné
,
H.
Mönkkönen
,
J.
Mönkkönen
,
J.
Li
,
J.
Kuball
,
E. J.
Adams
,
S.
Netzer
, et al
.
2012
.
Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset.
Blood
120
:
2269
2279
.
55
Starick
,
L.
,
F.
Riano
,
M. M.
Karunakaran
,
V.
Kunzmann
,
J.
Li
,
M.
Kreiss
,
S.
Amslinger
,
E.
Scotet
,
D.
Olive
,
G.
De Libero
,
T.
Herrmann
.
2017
.
Butyrophilin 3A (BTN3A, CD277)-specific antibody 20.1 differentially activates Vγ9Vδ2 TCR clonotypes and interferes with phosphoantigen activation.
Eur. J. Immunol.
47
:
982
992
.
56
Sandstrom
,
A.
,
C. M.
Peigné
,
A.
Léger
,
J. E.
Crooks
,
F.
Konczak
,
M. C.
Gesnel
,
R.
Breathnach
,
M.
Bonneville
,
E.
Scotet
,
E. J.
Adams
.
2014
.
The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human Vγ9Vδ2 T cells.
Immunity
40
:
490
500
.
57
Wang
,
H.
,
C. T.
Morita
.
2015
.
Sensor function for butyrophilin 3A1 in prenyl pyrophosphate stimulation of human Vγ2Vδ2 T cells.
J. Immunol.
195
:
4583
4594
.
58
Hayday
,
A.
,
N.
Roberts
.
2016
.
γδ T cell functions and biology.
In
Encyclopedia of Immunology.
M. J. F.
Ratcliffe
, ed.
Elsevier
, San Diego, CA, p.
325
335
.
59
Toulon
,
A.
,
L.
Breton
,
K. R.
Taylor
,
M.
Tenenhaus
,
D.
Bhavsar
,
C.
Lanigan
,
R.
Rudolph
,
J.
Jameson
,
W. L.
Havran
.
2009
.
A role for human skin-resident T cells in wound healing.
J. Exp. Med.
206
:
743
750
.
60
Landau
,
S. B.
,
W. I.
Aziz
,
J.
Woodcock-Mitchell
,
R.
Melamede
.
1995
.
V gamma (I) expression in human intestinal lymphocytes is restricted.
Immunol. Invest.
24
:
947
955
.
61
Di Marco Barros
,
R.
,
N. A.
Roberts
,
R. J.
Dart
,
P.
Vantourout
,
A.
Jandke
,
O.
Nussbaumer
,
L.
Deban
,
S.
Cipolat
,
R.
Hart
,
M. L.
Iannitto
, et al
.
2016
.
Epithelia use butyrophilin-like molecules to shape organ-specific γδ T cell compartments.
Cell
167
:
203
218
.
62
Melandri
,
D.
,
I.
Zlatareva
,
R. A. G.
Chaleil
,
R. J.
Dart
,
A.
Chancellor
,
O.
Nussbaumer
,
O.
Polyakova
,
N. A.
Roberts
,
D.
Wesch
,
D.
Kabelitz
, et al
.
2018
.
The γδTCR combines innate immunity with adaptive immunity by utilizing spatially distinct regions for agonist selection and antigen responsiveness.
Nat. Immunol.
19
:
1352
1365
.
63
Hirano
,
M.
,
P.
Guo
,
N.
McCurley
,
M.
Schorpp
,
S.
Das
,
T.
Boehm
,
M. D.
Cooper
.
2013
.
Evolutionary implications of a third lymphocyte lineage in lampreys.
Nature
501
:
435
438
.
64
Lewis
,
J. M.
,
M.
Girardi
,
S. J.
Roberts
,
S. D.
Barbee
,
A. C.
Hayday
,
R. E.
Tigelaar
.
2006
.
Selection of the cutaneous intraepithelial gammadelta+ T cell repertoire by a thymic stromal determinant.
Nat. Immunol.
7
:
843
850
.
65
Boyden
,
L. M.
,
J. M.
Lewis
,
S. D.
Barbee
,
A.
Bas
,
M.
Girardi
,
A. C.
Hayday
,
R. E.
Tigelaar
,
R. P.
Lifton
.
2008
.
Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells.
Nat. Genet.
40
:
656
662
.
66
Barbee
,
S. D.
,
M. J.
Woodward
,
G.
Turchinovich
,
J. J.
Mention
,
J. M.
Lewis
,
L. M.
Boyden
,
R. P.
Lifton
,
R.
Tigelaar
,
A. C.
Hayday
.
2011
.
Skint-1 is a highly specific, unique selecting component for epidermal T cells.
Proc. Natl. Acad. Sci. USA
108
:
3330
3335
.
67
Turchinovich
,
G.
,
A. C.
Hayday
.
2011
.
Skint-1 identifies a common molecular mechanism for the development of interferon-γ-secreting versus interleukin-17-secreting γδ T cells.
Immunity
35
:
59
68
.
68
Vantourout
,
P.
,
A.
Laing
,
M. J.
Woodward
,
I.
Zlatareva
,
L.
Apolonia
,
A. W.
Jones
,
A. P.
Snijders
,
M. H.
Malim
,
A. C.
Hayday
.
2018
.
Heteromeric interactions regulate butyrophilin (BTN) and BTN-like molecules governing γδ T cell biology.
Proc. Natl. Acad. Sci. USA
115
:
1039
1044
.
69
Kisielow
,
J.
,
L.
Tortola
,
J.
Weber
,
K.
Karjalainen
,
M.
Kopf
.
2011
.
Evidence for the divergence of innate and adaptive T-cell precursors before commitment to the αβ and γδ lineages.
Blood
118
:
6591
6600
.
70
Adams
,
E. J.
,
Y. H.
Chien
,
K. C.
Garcia
.
2005
.
Structure of a gammadelta T cell receptor in complex with the nonclassical MHC T22.
Science
308
:
227
231
.
71
Godder
,
K. T.
,
P. J.
Henslee-Downey
,
J.
Mehta
,
B. S.
Park
,
K. Y.
Chiang
,
S.
Abhyankar
,
L. S.
Lamb
.
2007
.
Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation.
Bone Marrow Transplant.
39
:
751
757
.
72
Correa
,
I.
,
M.
Bix
,
N. S.
Liao
,
M.
Zijlstra
,
R.
Jaenisch
,
D.
Raulet
.
1992
.
Most gamma delta T cells develop normally in beta 2-microglobulin-deficient mice.
Proc. Natl. Acad. Sci. USA
89
:
653
657
.
73
Benveniste
,
P. M.
,
S.
Roy
,
M.
Nakatsugawa
,
E. L. Y.
Chen
,
L.
Nguyen
,
D. G.
Millar
,
P. S.
Ohashi
,
N.
Hirano
,
E. J.
Adams
,
J. C.
Zúñiga-Pflücker
.
2018
.
Generation and molecular recognition of melanoma-associated antigen-specific human γδ T cells.
Sci. Immunol.
3
: eaav4036.
74
Medzhitov
,
R.
,
C. A.
Janeway
Jr
.
1997
.
Innate immunity: the virtues of a nonclonal system of recognition.
Cell
91
:
295
298
.
75
Salim
,
M.
,
T. J.
Knowles
,
R.
Hart
,
F.
Mohammed
,
M. J.
Woodward
,
C. R.
Willcox
,
M.
Overduin
,
A. C.
Hayday
,
B. E.
Willcox
.
2016
.
Characterization of a putative receptor binding surface on skint-1, a critical determinant of dendritic epidermal T cell selection.
J. Biol. Chem.
291
:
9310
9321
.
76
Yang
,
Y.
,
L.
Li
,
L.
Yuan
,
X.
Zhou
,
J.
Duan
,
H.
Xiao
,
N.
Cai
,
S.
Han
,
X.
Ma
,
W.
Liu
, et al
.
2019
.
A structural change in butyrophilin upon phosphoantigen binding underlies phosphoantigen-mediated Vγ9Vδ2 T cell activation.
Immunity
50
:
1043
1053.e5
.
77
Edelblum
,
K. L.
,
L.
Shen
,
C. R.
Weber
,
A. M.
Marchiando
,
B. S.
Clay
,
Y.
Wang
,
I.
Prinz
,
B.
Malissen
,
A. I.
Sperling
,
J. R.
Turner
.
2012
.
Dynamic migration of γδ intraepithelial lymphocytes requires occludin.
Proc. Natl. Acad. Sci. USA
109
:
7097
7102
.
78
Edelblum
,
K. L.
,
G.
Singh
,
M. A.
Odenwald
,
A.
Lingaraju
,
K.
El Bissati
,
R.
McLeod
,
A. I.
Sperling
,
J. R.
Turner
.
2015
.
γδ intraepithelial lymphocyte migration limits transepithelial pathogen invasion and systemic disease in mice.
Gastroenterology
148
:
1417
1426
.
79
Hoytema van Konijnenburg
,
D. P.
,
B. S.
Reis
,
V. A.
Pedicord
,
J.
Farache
,
G. D.
Victora
,
D.
Mucida
.
2017
.
Intestinal epithelial and intraepithelial T cell crosstalk mediates a dynamic response to infection.
Cell
171
:
783
794.e13
.
80
Chodaczek
,
G.
,
V.
Papanna
,
M. A.
Zal
,
T.
Zal
.
2012
.
Body-barrier surveillance by epidermal γδ TCRs.
Nat. Immunol.
13
:
272
282
.
81
Bueno
,
C.
,
C. D.
Lemke
,
G.
Criado
,
M. L.
Baroja
,
S. S.
Ferguson
,
A. K.
Rahman
,
C. D.
Tsoukas
,
J. K.
McCormick
,
J.
Madrenas
.
2006
.
Bacterial superantigens bypass Lck-dependent T cell receptor signaling by activating a Galpha11-dependent, PLC-beta-mediated pathway.
Immunity
25
:
67
78
.
82
Chen
,
J.
,
I. F.
López-Moyado
,
H.
Seo
,
C. J.
Lio
,
L. J.
Hempleman
,
T.
Sekiya
,
A.
Yoshimura
,
J. P.
Scott-Browne
,
A.
Rao
.
2019
.
NR4A transcription factors limit CAR T cell function in solid tumours.
Nature
567
:
530
534
.
83
Shires
,
J.
,
E.
Theodoridis
,
A. C.
Hayday
.
2001
.
Biological insights into TCRgammadelta+ and TCRalphabeta+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE).
Immunity
15
:
419
434
.
84
Gasser
,
S.
,
S.
Orsulic
,
E. J.
Brown
,
D. H.
Raulet
.
2005
.
The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor.
Nature
436
:
1186
1190
.
85
Vantourout
,
P.
,
C.
Willcox
,
A.
Turner
,
C. M.
Swanson
,
Y.
Haque
,
O.
Sobolev
,
A.
Grigoriadis
,
A.
Tutt
,
A.
Hayday
.
2014
.
Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway.
Sci. Transl. Med.
6
: 231ra49.
86
Ehrlich
,
L. I.
,
K.
Ogasawara
,
J. A.
Hamerman
,
R.
Takaki
,
A.
Zingoni
,
J. P.
Allison
,
L. L.
Lanier
.
2005
.
Engagement of NKG2D by cognate ligand or antibody alone is insufficient to mediate costimulation of human and mouse CD8+ T cells.
J. Immunol.
174
:
1922
1931
.
87
Strid
,
J.
,
S. J.
Roberts
,
R. B.
Filler
,
J. M.
Lewis
,
B. Y.
Kwong
,
W.
Schpero
,
D. H.
Kaplan
,
A. C.
Hayday
,
M.
Girardi
.
2008
.
Acute upregulation of an NKG2D ligand promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis.
Nat. Immunol.
9
:
146
154
.
88
Strid
,
J.
,
O.
Sobolev
,
B.
Zafirova
,
B.
Polic
,
A.
Hayday
.
2011
.
The intraepithelial T cell response to NKG2D-ligands links lymphoid stress surveillance to atopy.
Science
334
:
1293
1297
.
89
Correia
,
D. V.
,
M.
Fogli
,
K.
Hudspeth
,
M. G.
da Silva
,
D.
Mavilio
,
B.
Silva-Santos
.
2011
.
Differentiation of human peripheral blood Vδ1+ T cells expressing the natural cytotoxicity receptor NKp30 for recognition of lymphoid leukemia cells.
Blood
118
:
992
1001
.
90
Peckham
,
R. K.
,
R.
Brill
,
D. S.
Foster
,
A. L.
Bowen
,
J. A.
Leigh
,
T. J.
Coffey
,
R. J.
Flynn
.
2014
.
Two distinct populations of bovine IL-17+ T-cells can be induced and WC1+IL-17+γδ T-cells are effective killers of protozoan parasites.
Sci. Rep.
4
:
5431
.
91
Hsu
,
H.
,
C.
Chen
,
A.
Nenninger
,
L.
Holz
,
C. L.
Baldwin
,
J. C.
Telfer
.
2015
.
WC1 is a hybrid γδ TCR coreceptor and pattern recognition receptor for pathogenic bacteria.
J. Immunol.
194
:
2280
2288
.
92
Wencker
,
M.
,
G.
Turchinovich
,
R.
Di Marco Barros
,
L.
Deban
,
A.
Jandke
,
A.
Cope
,
A. C.
Hayday
.
2014
.
Innate-like T cells straddle innate and adaptive immunity by altering antigen-receptor responsiveness.
Nat. Immunol.
15
:
80
87
.
93
Sumida
,
H.
,
E.
Lu
,
H.
Chen
,
Q.
Yang
,
K.
Mackie
,
J. G.
Cyster
.
2017
.
GPR55 regulates intraepithelial lymphocyte migration dynamics and susceptibility to intestinal damage.
Sci. Immunol.
2
: eaao1135.
94
Witherden
,
D. A.
,
P.
Verdino
,
S. E.
Rieder
,
O.
Garijo
,
R. E.
Mills
,
L.
Teyton
,
W. H.
Fischer
,
I. A.
Wilson
,
W. L.
Havran
.
2010
.
The junctional adhesion molecule JAML is a costimulatory receptor for epithelial gammadelta T cell activation.
Science
329
:
1205
1210
.
95
Witherden
,
D. A.
,
M.
Watanabe
,
O.
Garijo
,
S. E.
Rieder
,
G.
Sarkisyan
,
S. J.
Cronin
,
P.
Verdino
,
I. A.
Wilson
,
A.
Kumanogoh
,
H.
Kikutani
, et al
.
2012
.
The CD100 receptor interacts with its plexin B2 ligand to regulate epidermal γδ T cell function.
Immunity
37
:
314
325
.
96
Li
,
Y.
,
S.
Innocentin
,
D. R.
Withers
,
N. A.
Roberts
,
A. R.
Gallagher
,
E. F.
Grigorieva
,
C.
Wilhelm
,
M.
Veldhoen
.
2011
.
Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation.
Cell
147
:
629
640
.
97
Jensen
,
K. D.
,
X.
Su
,
S.
Shin
,
L.
Li
,
S.
Youssef
,
S.
Yamasaki
,
L.
Steinman
,
T.
Saito
,
R. M.
Locksley
,
M. M.
Davis
, et al
.
2008
.
Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma.
Immunity
29
:
90
100
.
98
Pereira
,
P.
,
C.
Berthault
,
O.
Burlen-Defranoux
,
L.
Boucontet
.
2013
.
Critical role of TCR specificity in the development of Vγ1Vδ6.3+ innate NKTγδ cells.
J. Immunol.
191
:
1716
1723
.
99
Lombes
,
A.
,
A.
Durand
,
C.
Charvet
,
M.
Rivière
,
N.
Bonilla
,
C.
Auffray
,
B.
Lucas
,
B.
Martin
.
2015
.
Adaptive immune-like γ/δ T lymphocytes share many common features with their α/β T cell counterparts.
J. Immunol.
195
:
1449
1458
.
100
Ribot
,
J. C.
,
A.
deBarros
,
D. J.
Pang
,
J. F.
Neves
,
V.
Peperzak
,
S. J.
Roberts
,
M.
Girardi
,
J.
Borst
,
A. C.
Hayday
,
D. J.
Pennington
,
B.
Silva-Santos
.
2009
.
CD27 is a thymic determinant of the balance between interferon-gamma- and interleukin 17-producing gammadelta T cell subsets.
Nat. Immunol.
10
:
427
436
.
101
Ribot
,
J. C.
,
M.
Chaves-Ferreira
,
F.
d’Orey
,
M.
Wencker
,
N.
Gonçalves-Sousa
,
J.
Decalf
,
J. P.
Simas
,
A. C.
Hayday
,
B.
Silva-Santos
.
2010
.
Cutting edge: adaptive versus innate receptor signals selectively control the pool sizes of murine IFN-γ- or IL-17-producing γδ T cells upon infection.
J. Immunol.
185
:
6421
6425
.
102
Schmolka
,
N.
,
K.
Serre
,
A. R.
Grosso
,
M.
Rei
,
D. J.
Pennington
,
A. Q.
Gomes
,
B.
Silva-Santos
.
2013
.
Epigenetic and transcriptional signatures of stable versus plastic differentiation of proinflammatory γδ T cell subsets.
Nat. Immunol.
14
:
1093
1100
.
103
Shibata
,
K.
,
H.
Yamada
,
H.
Hara
,
K.
Kishihara
,
Y.
Yoshikai
.
2007
.
Resident Vdelta1+ gammadelta T cells control early infiltration of neutrophils after Escherichia coli infection via IL-17 production.
J. Immunol.
178
:
4466
4472
.
104
Shibata
,
K.
,
H.
Yamada
,
R.
Nakamura
,
X.
Sun
,
M.
Itsumi
,
Y.
Yoshikai
.
2008
.
Identification of CD25+ gamma delta T cells as fetal thymus-derived naturally occurring IL-17 producers.
J. Immunol.
181
:
5940
5947
.
105
O’Brien
,
R. L.
,
C. L.
Roark
,
W. K.
Born
.
2009
.
IL-17-producing gammadelta T cells.
Eur. J. Immunol.
39
:
662
666
.
106
Muñoz-Ruiz
,
M.
,
J. C.
Ribot
,
A. R.
Grosso
,
N.
Gonçalves-Sousa
,
A.
Pamplona
,
D. J.
Pennington
,
J. R.
Regueiro
,
E.
Fernández-Malavé
,
B.
Silva-Santos
.
2016
.
TCR signal strength controls thymic differentiation of discrete proinflammatory γδ T cell subsets.
Nat. Immunol.
17
:
721
727
.
107
Jouan
,
Y.
,
E. C.
Patin
,
M.
Hassane
,
M.
Si-Tahar
,
T.
Baranek
,
C.
Paget
.
2018
.
Thymic program directing the functional development of γδT17 cells.
Front. Immunol.
9
:
981
.
108
Sumaria
,
N.
,
C. L.
Grandjean
,
B.
Silva-Santos
,
D. J.
Pennington
.
2017
.
Strong TCRγδ signaling prohibits thymic development of IL-17A-secreting γδ T cells.
Cell Rep.
19
:
2469
2476
.
109
Hayes
,
S. M.
,
E. W.
Shores
,
P. E.
Love
.
2003
.
An architectural perspective on signaling by the pre-, alphabeta and gammadelta T cell receptors.
Immunol. Rev.
191
:
28
37
.
110
Lee
,
S. Y.
,
F.
Coffey
,
S. P.
Fahl
,
S.
Peri
,
M.
Rhodes
,
K. Q.
Cai
,
M.
Carleton
,
S. M.
Hedrick
,
H. J.
Fehling
,
J. C.
Zúñiga-Pflücker
, et al
.
2014
.
Noncanonical mode of ERK action controls alternative αβ and γδ T cell lineage fates.
Immunity
41
:
934
946
.
111
Lu
,
Y.
,
M. C.
Zhong
,
J.
Qian
,
V.
Calderon
,
M.
Cruz Tleugabulova
,
T.
Mallevaey
,
A.
Veillette
.
2019
.
SLAM receptors foster iNKT cell development by reducing TCR signal strength after positive selection.
Nat. Immunol.
20
:
447
457
.
112
Michel
,
M. L.
,
D. J.
Pang
,
S. F.
Haque
,
A. J.
Potocnik
,
D. J.
Pennington
,
A. C.
Hayday
.
2012
.
Interleukin 7 (IL-7) selectively promotes mouse and human IL-17-producing γδ cells.
Proc. Natl. Acad. Sci. USA
109
:
17549
17554
.
113
Nakamura
,
M.
,
K.
Shibata
,
S.
Hatano
,
T.
Sato
,
Y.
Ohkawa
,
H.
Yamada
,
K.
Ikuta
,
Y.
Yoshikai
.
2015
.
A genome-wide analysis identifies a notch-RBP-Jκ-IL-7Rα axis that controls IL-17-producing γδ T cell homeostasis in mice.
J. Immunol.
194
:
243
251
.
114
Zarin
,
P.
,
T. S.
In
,
E. L.
Chen
,
J.
Singh
,
G. W.
Wong
,
M.
Mohtashami
,
D. L.
Wiest
,
M. K.
Anderson
,
J. C.
Zúñiga-Pflücker
.
2018
.
Integration of T-cell receptor, Notch and cytokine signals programs mouse γδ T-cell effector differentiation.
Immunol. Cell Biol.
96
:
994
1007
.
115
Schmolka
,
N.
,
P. H.
Papotto
,
P. V.
Romero
,
T.
Amado
,
F. J.
Enguita
,
A.
Amorim
,
A. F.
Rodrigues
,
K. E.
Gordon
,
A. S.
Coroadinha
,
M.
Boldin
, et al
.
2018
MicroRNA-146a controls functional plasticity in γδ T cells by targeting NOD1.
Sci. Immunol.
3
:
eaao1392
.
116
Zuberbuehler
,
M. K.
,
M. E.
Parker
,
J. D.
Wheaton
,
J. R.
Espinosa
,
H. R.
Salzler
,
E.
Park
,
M.
Ciofani
.
2019
.
The transcription factor c-Maf is essential for the commitment of IL-17-producing γδ T cells. [Published erratum appears in 2019 Nat. Immunol. 20: 663.]
Nat. Immunol.
20
:
73
85
.
117
Savage
,
A. K.
,
M. G.
Constantinides
,
J.
Han
,
D.
Picard
,
E.
Martin
,
B.
Li
,
O.
Lantz
,
A.
Bendelac
.
2008
.
The transcription factor PLZF directs the effector program of the NKT cell lineage.
Immunity
29
:
391
403
.
118
Sumaria
,
N.
,
S.
Martin
,
D. J.
Pennington
.
2019
.
Developmental origins of murine γδ T-cell subsets.
Immunology
156
:
299
304
.
119
Mensurado
,
S.
,
M.
Rei
,
T.
Lança
,
M.
Ioannou
,
N.
Gonçalves-Sousa
,
H.
Kubo
,
M.
Malissen
,
V.
Papayannopoulos
,
K.
Serre
,
B.
Silva-Santos
.
2018
.
Tumor-associated neutrophils suppress pro-tumoral IL-17+ γδ T cells through induction of oxidative stress.
PLoS Biol.
16
: e2004990.
120
St Leger
,
A. J.
,
J. V.
Desai
,
R. A.
Drummond
,
A.
Kugadas
,
F.
Almaghrabi
,
P.
Silver
,
K.
Raychaudhuri
,
M.
Gadjeva
,
Y.
Iwakura
,
M. S.
Lionakis
,
R. R.
Caspi
.
2017
.
An ocular Commensal protects against corneal infection by driving an interleukin-17 response from mucosal γδ T cells.
Immunity
47
:
148
158.e5
.
121
Kohlgruber
,
A. C.
,
S. T.
Gal-Oz
,
N. M.
LaMarche
,
M.
Shimazaki
,
D.
Duquette
,
H. F.
Koay
,
H. N.
Nguyen
,
A. I.
Mina
,
T.
Paras
,
A.
Tavakkoli
, et al
.
2018
.
γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis. [Published erratum appears in 2019 Nat. Immunol. 20: 373.]
Nat. Immunol.
19
:
464
474
.
122
Sandrock
,
I.
,
A.
Reinhardt
,
S.
Ravens
,
C.
Binz
,
A.
Wilharm
,
J.
Martins
,
L.
Oberdörfer
,
L.
Tan
,
S.
Lienenklaus
,
B.
Zhang
, et al
.
2018
.
Genetic models reveal origin, persistence and non-redundant functions of IL-17-producing γδ T cells.
J. Exp. Med.
215
:
3006
3018
.
123
Linehan
,
J. L.
,
O. J.
Harrison
,
S. J.
Han
,
A. L.
Byrd
,
I.
Vujkovic-Cvijin
,
A. V.
Villarino
,
S. K.
Sen
,
J.
Shaik
,
M.
Smelkinson
,
S.
Tamoutounour
, et al
.
2018
.
Non-classical immunity controls microbiota impact on skin immunity and tissue repair.
Cell
172
:
784
796.e18
.
124
Jin
,
C.
,
G. K.
Lagoudas
,
C.
Zhao
,
S.
Bullman
,
A.
Bhutkar
,
B.
Hu
,
S.
Ameh
,
D.
Sandel
,
X. S.
Liang
,
S.
Mazzilli
, et al
.
2019
.
Commensal microbiota promote lung cancer development via γδ T cells.
Cell
176
:
998
1013.e16
.
125
McKenzie
,
D. R.
,
E. E.
Kara
,
C. R.
Bastow
,
T. S.
Tyllis
,
K. A.
Fenix
,
C. E.
Gregor
,
J. J.
Wilson
,
R.
Babb
,
J. C.
Paton
,
A.
Kallies
, et al
.
2017
.
IL-17-producing γδ T cells switch migratory patterns between resting and activated states.
Nat. Commun.
8
:
15632
.
126
Mielke
,
L. A.
,
S. A.
Jones
,
M.
Raverdeau
,
R.
Higgs
,
A.
Stefanska
,
J. R.
Groom
,
A.
Misiak
,
L. S.
Dungan
,
C. E.
Sutton
,
G.
Streubel
, et al
.
2013
.
Retinoic acid expression associates with enhanced IL-22 production by γδ T cells and innate lymphoid cells and attenuation of intestinal inflammation.
J. Exp. Med.
210
:
1117
1124
.
127
Krishnan
,
S.
,
I. E.
Prise
,
K.
Wemyss
,
L. P.
Schenck
,
H. M.
Bridgeman
,
F. A.
McClure
,
T.
Zangerle-Murray
,
C.
O’Boyle
,
T. A.
Barbera
,
F.
Mahmood
, et al
.
2018
.
Amphiregulin-producing γδ T cells are vital for safeguarding oral barrier immune homeostasis.
Proc. Natl. Acad. Sci. USA
115
:
10738
10743
.
128
Guo
,
X. J.
,
P.
Dash
,
J. C.
Crawford
,
E. K.
Allen
,
A. E.
Zamora
,
D. F.
Boyd
,
S.
Duan
,
R.
Bajracharya
,
W. A.
Awad
,
N.
Apiwattanakul
, et al
.
2018
.
Lung γδ T cells mediate protective responses during neonatal influenza infection that are associated with type 2 immunity.
Immunity
49
:
531
544.e6
.
129
Caccamo
,
N.
,
C.
La Mendola
,
V.
Orlando
,
S.
Meraviglia
,
M.
Todaro
,
G.
Stassi
,
G.
Sireci
,
J. J.
Fournié
,
F.
Dieli
.
2011
.
Differentiation, phenotype, and function of interleukin-17-producing human Vγ9Vδ2 T cells.
Blood
118
:
129
138
.
130
Tyler
,
C. J.
,
N. E.
McCarthy
,
J. O.
Lindsay
,
A. J.
Stagg
,
B.
Moser
,
M.
Eberl
.
2017
.
Antigen-presenting human γδ T cells promote intestinal CD4+ T cell expression of IL-22 and mucosal release of calprotectin.
J. Immunol.
198
:
3417
3425
.
131
Mayassi
,
T.
,
K.
Ladell
,
H.
Gudjonson
,
J. E.
McLaren
,
D. G.
Shaw
,
M. T.
Tran
,
J. J.
Rokicka
,
I.
Lawrence
,
J. C.
Grenier
,
V.
van Unen
, et al
.
2019
.
Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease.
Cell
176
:
967
981.e19
.
132
Girardi
,
M.
,
D. E.
Oppenheim
,
C. R.
Steele
,
J. M.
Lewis
,
E.
Glusac
,
R.
Filler
,
P.
Hobby
,
B.
Sutton
,
R. E.
Tigelaar
,
A. C.
Hayday
.
2001
.
Regulation of cutaneous malignancy by gammadelta T cells.
Science
294
:
605
609
.
133
Liu
,
Z.
,
I. E.
Eltoum
,
B.
Guo
,
B. H.
Beck
,
G. A.
Cloud
,
R. D.
Lopez
.
2008
.
Protective immunosurveillance and therapeutic antitumor activity of gammadelta T cells demonstrated in a mouse model of prostate cancer.
J. Immunol.
180
:
6044
6053
.
134
Gentles
,
A. J.
,
A. M.
Newman
,
C. L.
Liu
,
S. V.
Bratman
,
W.
Feng
,
D.
Kim
,
V. S.
Nair
,
Y.
Xu
,
A.
Khuong
,
C. D.
Hoang
, et al
.
2015
.
The prognostic landscape of genes and infiltrating immune cells across human cancers.
Nat. Med.
21
:
938
945
.
135
Tosolini
,
M.
,
F.
Pont
,
M.
Poupot
,
F.
Vergez
,
M. L.
Nicolau-Travers
,
D.
Vermijlen
,
J. E.
Sarry
,
F.
Dieli
,
J. J.
Fournié
.
2017
.
Assessment of tumor-infiltrating TCRVγ9Vδ2 γδ lymphocyte abundance by deconvolution of human cancers microarrays.
Oncoimmunology
6
: e1284723.
136
Dalessandri
,
T.
,
G.
Crawford
,
M.
Hayes
,
R.
Castro Seoane
,
J.
Strid
.
2016
.
IL-13 from intraepithelial lymphocytes regulates tissue homeostasis and protects against carcinogenesis in the skin.
Nat. Commun.
7
:
12080
.
137
Crawford
,
G.
,
M. D.
Hayes
,
R. C.
Seoane
,
S.
Ward
,
T.
Dalessandri
,
C.
Lai
,
E.
Healy
,
D.
Kipling
,
C.
Proby
,
C.
Moyes
, et al
.
2018
.
Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response.
Nat. Immunol.
19
:
859
870
.

A.C.H. is a cofounder and board member of Gamma Delta Therapeutics and of ImmunoQure AG.