Memory CD8+ T cells promote protective immunity against viruses or cancer. Our field has done a terrific job identifying how CD8+ T cell memory forms in response to Ag. However, many studies focused on systems in which inflammation recedes over time. These situations, while relevant, do not cover all situations in which CD8+ T cell memory is relevant. It is increasingly clear that CD8+ T cells with a memory phenotype form in response to infections with extensive or prolonged tissue inflammation, for example, influenza, herpes, and more recently, COVID-19. In these circumstances, inflammatory mediators expectedly affect forming memory CD8+ T cells, especially in tissues in which pathogens establish. Notwithstanding recent important discoveries, many outstanding questions on how inflammation shapes CD8+ T cell memory remain unanswered. We will discuss, in this review, what is already known and the next steps to understand how inflammation influences CD8+ T cell memory.

Immunological memory can be characterized by the presence of Ag-specific adaptive immune cells with enhanced ability to respond to secondary Ag encounter. The acquisition of immunological memory is paramount for the protection against pathogen reinfections and is the desired goal of vaccination protocols (13). Although the development of humoral immunity (i.e., B cell–dependent) promotes the protection against many infections and is the basis of most existing vaccines, there are diseases for which either humoral immunity is less relevant (e.g., tuberculosis) or B cell–inducing vaccines do not exist (e.g., HIV, malaria) (4). In situations for which the relevant Ag is present inside cells, the development of cytotoxic memory CD8+ T cells is fundamental, given CD8+ T cells are key in cell-mediated immunity and the clearance of intracellular pathogens (2). This is also true for cancer, for which the elimination of tumor cells requires CD8+ T cells in many cases, and the harnessing of CD8+ T cells with memory-like characteristics promotes enhanced tumor control (5).

Understanding how CD8+ T cell memory forms has been and still is a fundamental part of the cellular immunology field. Thanks to seminal works, we have a consensual view of how Ag-specific memory CD8+ T cells are generated. Notwithstanding these fundamental discoveries, they mostly used model infections and immunizations for which acute inflammation is present. Acute inflammation, albeit a relevant factor, recedes swiftly over time because of quick pathogen or Ag elimination. It has been increasingly appreciated, also, that elements of the tissue microenvironment help shape CD8+ T cell responses (69). In response to infections that induce increased tissue inflammation, memory CD8+ T cells are found. This is true in the context of influenza (1012) or herpes (13, 14). Therefore, it is likely that the quality, duration, and intensity of the inflammatory context will differentially affect memory CD8+ T cell generation and maintenance. How and whether memory CD8+ T cells form and respond to distinct inflammatory stimuli is currently being investigated by many groups, and we are only now beginning to understand these concepts. This is especially important nowadays, as COVID-19 (caused by the SARS-CoV-2 virus) protection may rely on CD8+ T cell memory responses (15), and this disease is characterized by intense tissue inflammatory responses (16, 17). In this review, we will focus on how inflammation affects the establishment and function of memory CD8+ T cells. We will also discuss how established memory CD8+ T cell populations are influenced by systemic or local inflammation. Finally, we will convey the next steps needed for our complete understanding of how inflammation shapes the memory CD8+ T cell pool, highlighting the main unexplored information “seas” on this matter.

In the past few decades, many papers unveiled how Ag-specific CD8+ T cells clonally expand and differentiate into terminal effectors (TEs) or multiple memory cell subsets. Memory CD8+ T cells survive in the long-term and display enhanced responsivity to secondary Ag encounter. Many cell-intrinsic and -extrinsic signals are instrumental in the effector-to-memory transition and memory CD8+ T cell survival.

Metabolic and transcriptional regulation of CD8+ T cell effector expansion and memory precursor generation

Naive CD8+ T cells are generated in the thymus and migrate to the periphery. After engagement with cognate Ag (together with costimulatory pathways and tertiary signals), CD8+ T cells display many metabolic and transcriptional changes (18). Recently activated CD8+ T cells first increase oxidative phosphorylation, quickly followed by a switch to aerobic glycolysis, a metabolic state characterized by diversion away from mitochondrial respiration pathways (19). These changes are accompanied by activation and robust clonal expansion (20). Increased aerobic glycolysis in effector cells allows energy production to be quicker in response to stimulation and simultaneously promotes the biosynthesis of proteins and other molecules needed to produce effector molecules (19).

Throughout the acute Ag effector phase, Ag-specific CD8+ T cells expand but not uniformly. Already at the early effector phase, effector CD8+ T cells can be distinguished by the expression level of IL-2Rα or CD25. CD25hi early effectors are sensitive to IL-2. As a result, they proliferate more extensively but are more prone to apoptosis. In contrast, CD25lo early effectors are less sensitive to IL-2. These cells, conversely, increase the expression of IL-7Rα or CD127 and L-selectin (CD62L) (21). CD127, for instance, marks a subset of effector CD8+ T cells that can survive T cell contraction and give rise to memory CD8+ T cells; these cells are deemed “memory precursors” (MPs) (22, 23). Conversely, effector CD8+ T cells that express the killer cell lectin-like receptor G 1 (KLRG1) will mostly contract; these effector CD8+ cells are called TEs (23). Distinct molecules drive the fate of effector CD8+ T cells into the MP versus the TE phenotype. For example, expression of the transcription factors Blimp-1 and ZEB2 promote the TE phenotype in CD8+ T cells (24, 25). In contrast, the transcription factors TCF1, LEF-1, and Bcl-6 induce the MP phenotype in these cells (2628). Overall, the terminal differentiation of CD8+ T cells is reliant on an increase in pathways related to effector function. Conversely, the induction of an MP phenotype is correlated with the acquisition of quiescence and stemness at the expense of effector function. Thus, both effector CD8+ T cell groups are important, one for the direct pathogen elimination during acute responses and the other for generation of memory CD8+ T cells.

Circulating memory CD8+ T cell subsets

After Ag clearance, most TE CD8+ T cells die. It should be noted that CD8+ T cell contraction does not depend on Ag clearance because it also occurs when pathogen is not completely eliminated (29, 30). Distinct memory CD8+ T cell subsets arise from MP cells, and they can be divided based on distinct aspects. There is currently much talk about how we as a scientific community should define these subsets (31, 32). In this study, we will focus on migratory properties to subdivide memory CD8+ T cells (Table I). Two memory CD8+ T cell subsets were initially defined. Central memory CD8+ T cells (Tcm), which express the secondary lymphoid organ-homing molecules CCR7 and CD62L, are mainly found within the spleen and lymph nodes, lack immediate effector function and have increased ability to generate secondary immune responses. Effector memory CD8+ T cells (Tem) lack expression of these markers, displaying receptors that promote the migration back and from other tissues and have a better ability to readily produce cytokines (3335). The current view of circulating memory CD8+ T cells is much more complex. The Tcm subset is still somewhat homogeneous, but they are not the only subpopulation of memory CD8+ T cells with quiescence and stemness. In humans and nonhuman primates, a population of stem cell–like memory CD8+ T cells (Tscm) has similar functional characteristics as Tcm but is phenotypically similar to naive CD8+ T cells (36). As for the previous Tem pool, they currently comprise an amalgam of three main subsets. Many of the cells found in nonlymphoid tissues reside long-term in these sites; these cells are now denominated tissue-resident memory CD8+ T cells (Trm); there is more on this subset below. Among the non-Tcm found in the circulation and lymphoid organs, two subsets are found. Tem are derived from MPs, do not express lymph node–homing molecules, and have the characteristics previously described (i.e., lower stemness and half-life and quicker cytokine production) (37). More recently, a new population of non-Tcm was described to have an identical phenotype as TE cells but was found long after Ag clearance. These cells, called “long-lived effector cells” (LLECs) (38, 39), perform superior recall responses against Ag, despite decreased proliferation (38). Tcm, Tem, and LLEC all rely on IL-15 for their survival (38, 40). Tcm and Tem also display IL-7R in their surfaces and rely on this cytokine for survival, mainly through the antiapoptotic protein Bcl-2 and expression of Aquaporin-9 (4144).

Table I.

Main characteristics of the distinct memory CD8+ T cell subsets

Memory Subset Main Characteristics Phenotypic Markers 
Tcm Quiescence, stemness, quick reactivation and proliferation upon secondary Ag, recirculate between lymphoid organs and blood CD44+, CD62L+, CCR7+, TCF1hi, IL-7Ra+, CD45RA- (humans) 
Tscm Development occurs early after clonal activation, phenotypic characteristics resembling naive CD8+ T cells, highly, quiescent, stemness, recirculate between lymphoid organs and blood CD44lo, CD62L+, CD45RA+ (humans) 
Tem Heightened capacity to produce cytokines upon secondary Ag, recirculate between lymphoid organs, blood and nonlymphoid organs, shorter lived, decreased stemness CD44+, CD62L, IL-7Ra+, KLRG1 
LLECs May arise from TEs, highest ability to respond to secondary Ag, do not enter nonlymphoid tissues (mostly confined to blood and spleen red pulp) CD44+, CD62L, IL-7Ra, KLRG1+, CX3CR1hi 
Trm Do not recirculate (mostly found in nonlymphoid organs, some in lymphoid organs), quick mediators of secondary immunity to local insults (e.g., barrier infections), high expression of tissue residency markers and transcriptional signatures (e.g., Hobit/Blimp1), can be defined (in mice) by lack of recirculation upon parabiosis surgery or negative intravascular labeling CD44+, CD62L, intravascular Ab (mice), CD69/CD103+ (tissue dependent), KLF2lo, Hobit/Blimp1+ (tissue dependent) 
Memory Subset Main Characteristics Phenotypic Markers 
Tcm Quiescence, stemness, quick reactivation and proliferation upon secondary Ag, recirculate between lymphoid organs and blood CD44+, CD62L+, CCR7+, TCF1hi, IL-7Ra+, CD45RA- (humans) 
Tscm Development occurs early after clonal activation, phenotypic characteristics resembling naive CD8+ T cells, highly, quiescent, stemness, recirculate between lymphoid organs and blood CD44lo, CD62L+, CD45RA+ (humans) 
Tem Heightened capacity to produce cytokines upon secondary Ag, recirculate between lymphoid organs, blood and nonlymphoid organs, shorter lived, decreased stemness CD44+, CD62L, IL-7Ra+, KLRG1 
LLECs May arise from TEs, highest ability to respond to secondary Ag, do not enter nonlymphoid tissues (mostly confined to blood and spleen red pulp) CD44+, CD62L, IL-7Ra, KLRG1+, CX3CR1hi 
Trm Do not recirculate (mostly found in nonlymphoid organs, some in lymphoid organs), quick mediators of secondary immunity to local insults (e.g., barrier infections), high expression of tissue residency markers and transcriptional signatures (e.g., Hobit/Blimp1), can be defined (in mice) by lack of recirculation upon parabiosis surgery or negative intravascular labeling CD44+, CD62L, intravascular Ab (mice), CD69/CD103+ (tissue dependent), KLF2lo, Hobit/Blimp1+ (tissue dependent) 

Tissue-resident memory CD8+ T cells

Over the last two decades, important studies defined that some memory CD8+ T cells permanently reside in nonlymphoid tissues (45, 46). Trm can be defined, in many cases, by tissue residency markers, such as CD69 and/or CD103, with a concomitant lack of CD62L and KLRG1 (30). Trm are defined in mouse models through either lack of intravascular Ab staining (47) or by lack of recirculation after parabiosis surgery (48). The notable exception for intravascular labeling is the liver, where Trm (defined as resident by parabiosis) are positioned in the intravascular sinusoids (49). Trm function by patrolling their respective tissues, searching for cognate peptides from secondary exposure. Therefore, they act as the first layer of defense in barrier tissues, inducing a state of immune alert via quick cytokine production after Ag re-encounter (5053).

Trm can be found virtually everywhere in the organism. This includes epithelial and nonepithelial sites (10, 30, 48, 54) and secondary lymphoid organs (55). Trm widely vary in their phenotype. Although, in epithelial sites, most Trm coexpress CD69 and CD103, in other nonlymphoid tissues, CD103+ cells are mostly absent, and many Trm do not express CD69 as well (54). Liver Trm, for instance, are gated based on CXCR6 expression (56). These variations in the expression of “residency” markers likely reflect the distinct microenvironments of each organ.

The pathways needed for Trm establishment are still being unveiled, and akin to their phenotype, they are likely distinct between tissues. For most epithelial sites, signaling through TGF-β is necessary (11, 30, 57, 58). In contrast, Trm generation in the liver is less dependent on this cytokine (49, 59). The need for cognate Ag signaling inside the tissue is also organ-dependent. Whereas in the skin, female reproductive tract, and gut their microenvironment, signals are sufficient to support Trm generation (50, 60, 61), lung Trm require Ag inside the tissue (62, 63). The long-term survival of Trm may also have organ-dependent requirements, and this is perfectly exemplified by the role of IL-15. After lymphocytic choriomeningitis virus (LCMV) infection, whereas IL-15 promotes Trm survival in the salivary gland and kidney, it is dispensable for their maintenance in the small intestine, female reproductive tract, and pancreas (64). These findings, in many cases, are the result of studies that used either immunization Ag plus adjuvant or the model virus LCMV. In both these models, only a transient inflammatory response occurs, rather than what happens in response to pathogens of medical relevance, such as ones directly infecting barrier tissues.

CD8+ T cell activation occurs in lymph nodes or spleen through Ag presentation by dendritic cells (DCs). DCs can either be resident in these organs or migrate from barrier tissues where they picked up Ag (6568). The microanatomical relocalization of DCs to T cell–rich areas is a fundamental step of CD8+ T cell activation (6973). Past research has defined that, in most cases, DCs recognize and capture cognate Ag in the port of entry (systemic or local), migrate to proximal lymphoid organs toward T cell–rich areas, and present Ag (72, 73). Whether inflammation affects this was not entirely clear, although lymph node inflammation is important for the full activation of CD8+ T cells (74). Moreover, inflammatory cytokines are considered an additional signal to TCR and costimulation for maximal CD8+ T cell proliferation (75). A recent study has investigated this, using sophisticated imaging tools. Surprisingly, in response to type I inflammation induced by TLR, lymph node-resident DCs (rather than migratory ones) are crucial for Ag delivery and initial activation of CD8+ T cells. Resident DCs relocate to T cell zones through CCR7 signaling, which allows for quick Ag presentation. Further highlighting the importance of inflammation, upon type I signals, monocytes infiltrate lymph nodes via CCR2 through local blood vessels. Inside lymph nodes, monocytes enter the T cell zone and secrete inflammatory cytokines to boost T cell activation (76), confirming previous studies showing the ability of these cells to infiltrate Ag-draining lymph nodes (77, 78). Importantly, these inflammatory monocytes do not distribute equally inside the T cell zone. This promotes distinct microenvironments within these lymphoid organs that are based on the intensity of inflammatory signals. Consequently, effector CD8+ T cells with distinct phenotypes can be found in these intranodal microenvironments, showing that inflammatory signals not only help CD8+ T cell effector function but also direct their heterogeneity (76). This divergent early CD8+ T cell effector programming may also impact the generation of CD8+ T cell memory. This is suggested by the clear distinction in TCF1, a promemory transcription factor (79), observed between CD8+ T cells in distinct microenvironments (76). The interplay between inflammatory signals, TCR engagement, and CD8+ T cell function is also highlighted by studies showing that a concerted action of both pathways shape how some early effector CD8+ T cells undergo Bim-dependent apoptosis (80). TCR signal strength and Ag availability, conversely, can dictate how effector CD8+ T cells develop intracellular proinflammatory pathways (3).

The intensity and quality of inflammation dictate not only the magnitude of CD8+ T cell effector expansion but also fine-tune their phenotype and impact their different functional aspects (23, 8183). This is important to promote the elimination of infected cells, given inflammation-induced chemokine and integrin ligand upregulation promote effector CD8+ T cell infiltration into nonlymphoid tissues and pathogen killing (8488). Consequently, the phenotype and function of effector CD8+ T cells vary depending on the type of infection. For example, whereas in response to vesicular stomatitis virus a greater proportion of effector CD8+ T cells differentiate into MP cells, in response to Listeria, almost all effector CD8+ T cells have a TE phenotype (89). Because inflammation is dependent on pathogen load, in many cases, the infection intensity is the defining feature of the effector CD8+ T cell response. A relevant example is COVID-19, in which the presence of polyfunctional SARS-CoV-2–specific CD8+ T cells are associated with recovery from disease (90, 91) and the magnitude of Ag-specific CD8+ T cells correlates with viral load (91). However, the correlation between inflammatory molecules and the expression of effector molecules in SARS-CoV-2–specific CD8+ T cells was weak (91). This suggests a more complex interplay between lung inflammation, Ag load, and effector CD8+ T cell responses during COVID-19.

Beyond affecting their effector expansion, the inflammatory context induced by various diseases can determine how and whether CD8+ T cell memory is formed. In addition, memory CD8+ T cells face distinct levels of inflammation in different tissues that also affects their long-term survival and secondary function.

How inflammation shapes memory CD8+ T cell generation

The effector-to-memory transition typically occurs during the peak of effector response, when MP cells arise (22). Even in the context of LCMV infection, the presence of proinflammatory cytokines (namely, prolonged IL-2, type I IFN, and IL-12 stimulation) divert effector CD8+ T cells away from the memory phenotype (23, 92, 93). The sensing of these cytokines, however, cannot be interpreted separately from cognate Ag. Indeed, reduced TCR signal strength resulted in increased MP accumulation even in the presence of inflammatory cytokines (3). The effect of inflammation on MP cells may also be context-dependent. Different from acute viral infection, immunization with inflammation-inducing adjuvants (e.g., CpG) do not affect the numbers of MPs, rather they promote an increase of TE cells (94).

In contrast, another signal typically associated with tissue inflammation, eATP, was shown by us to promote the MP phenotype and transition to memory in CD8+ T cells through the P2RX7 receptor (95). The role of eATP sensing for CD8+ T cells is likely complex and may involve autocrine release of eATP by CD8+ T cells via the hemichannel Pannexin-1 (95, 96). In this case, inflammation-derived eATP may not be relevant for memory generation, at least in the presence of less aggressive pathogens. Whether this is true in the presence of infections that induce enhanced or prolonged tissue inflammation, such as influenza in the lung or Yersinia in the gut, remains to be defined. In addition, despite preferential expression of P2RX7 in MP cells, many early effector CD8+ T cells also express P2RX7 (59, 95), and it is reasonable to assume that not all of them will become MP cells. What is the effect of eATP sensing on effector CD8+ T cells that do not become MP cells? Like MPs, are these cells able to release eATP via Pannexin-1? These will be important questions to be answered and may help us understand whether CD8+ T cells rely on eATP for memory generation in the context of excessive inflammation-derived eATP.

Another inflammatory signal likely sensed by forming memory CD8+ T cells is DNA from viral origin or from host/CD8+ T cells themselves. Recognition of DNA and engagement of the cGAS–STING pathway can induce cell death in certain cell types (97). Contrary to this, CD8+ T cell cGAS–STING activation promotes the generation of Tcm phenotype CD8+ T cells in humans (98). Cytosolic DNA can accumulate in effector CD8+ T cells, and simultaneous engagement of DNA repair pathways is likely important for memory CD8+ T cell generation. Indeed, a DNA repair gene signature is associated with memory CD8+ T cell generation (99). This may suggest that increased DNA repair helps curb the intensity of the cGAS–STING activation to prevent undesirable effects (i.e., cell death).

Many pathogens induce a localized immune response. Protective immunity in these cases relies on Trm, and tissue inflammation context influences how and whether Trm are formed. In the small intestine, two major inflammation-modulating factors affect Trm generation: the local microbiota and the presence of regulatory T cells (Tregs). The gut microbiota contains specific bacteria that can promote the accumulation of intestine Trm (100). Moreover, Trm specific for microbiota Ags found in the gut can promote protection against certain oral infections and tumors (101). In different circumstances, however, microbiota may diminish Trm accumulation and responses. For example, transient elimination of microbiota favors CD8+ Trm responses to Listeria-encoded Ags (102).

Although peripheral Treg expansion may be deleterious for gut Trm accumulation in determined contexts (103), in response to infections inducing type I inflammation, expansion of type 1 Tregs is important for the induction of CD8+ Trm by increasing the availability of bioactive TGF-β in the small intestine microenvironment (104). Treg depletion also leads to reduced Trm numbers in the CNS upon viral infection (105). The apparent lesson from these studies is that tissue inflammation is, in many cases, important for Trm development, but in controlled levels; in a somewhat similar manner as for circulating memory CD8+ T cells, excessive type 1 inflammation diverts tissue-seeding CD8+ T cells to a terminal phenotype. Agreeing with this notion, disproportionate inflammation limits the acquisition of memory traits and favors terminal exhaustion in CD8+ T cells during chronic LCMV infection (106). Moreover, CD8+ T cell diversion toward terminal exhaustion relies on expression of inflammation-associated transcriptional features, including T-bet and Tox upregulation (107).

Excessive inflammation may be deleterious for the generation of memory CD8+ T cells. Response to SARS-CoV-2, however, may induce a more complex relation between inflammation and CD8+ T cell memory. Many studies suggest that CD4+ and CD8+ T cell memory, elicited by past exposure or immunization, is crucial to promote long-term protection against the virus (90, 108111). Aside from a potential contribution of pre-existing memory CD8+ T cells specific for cross-reactive coronavirus Ags (112), much of the CD8+ T cell response to SARS-CoV-2 is mediated by newly activated clones (91). In convalescent patients, SARS-CoV-2–specific CD8+ T cells are enriched for the Tscm pool. In high-prevalence clones, these cells are skewed toward a Temra (i.e., effector memory cells re-expressing CD45RA) and Tem phenotypes, with a low prevalence in quiescent cells. In airway samples from patients, CD8+ T cells with a Trm phenotype can be found, and higher frequency of these cells correlated with younger age and survival (113). Future studies focusing on how memory CD8+ T cells form and function in both circulation and tissues of SARS-CoV-2–infected hosts will be needed.

Role of inflammation in memory CD8+ T cell maintenance and reactivation

Inflammatory signals can affect not only the generation of memory CD8+ T cells but also their maintenance. In many circumstances, bystander infections or insults lead to increased secretion of inflammatory mediators that can affect existing memory CD8+ T cells. A straight-forward example is sepsis, which induces preferential attrition of memory CD8+ T cells (114). The effect of bystander inflammation is usually more prevalent in barrier tissues, which are often the sites of new infections. An example is the lung, where epithelial cells infected with influenza increase their production and secretion of TSLP. TSLP, despite positively modulating naive CD8+ T cell survival in vitro, negatively impacts existing lung CD8+ Trm (115). TSLP directly represses the expression of the transcription factors Runx2 and Egr2, both important for antiviral CD8+ T cell homeostasis (116, 117). TSLP activity also diminished the expression of Pannexin-1, which can influence CD8+ T cell mitochondrial homeostasis in the context of IL-15 (95) and may influence memory CD8+ T cell maintenance (96). Pannexin-1, as explained above, mediates the export of eATP in CD8+ T cells. We have found the eATP signaling through P2RX7 promotes the long-term maintenance of established Trm by using mouse LCMV (59), which does not, however, induce relevant lung Trm populations (63). Future studies will be necessary to assess whether P2RX7 (and Pannexin-1) are required for the maintenance of lung Trm populations. If this is true, it will be important to assess whether TSLP also influences eATP sensing pathways in lung Trm. Mirroring circulating memory CD8+ T cells (118), lung Trm maintenance relies on mitochondrial fitness, more specifically on the expression of the transcription factor Bhlhe40 (10). The lung, like other mucosal tissues and tumors, displays limited nutrients (e.g., glucose) and increased baseline inflammation (119, 120). The induction of stress pathways in lung Trm is likely important for the tissue-specific function of Bhlhe40, which is a stress-responsive protein.

Conversely, memory CD8+ T cells can be activated in response to bystander inflammation in certain situations, inducing an effector T cell–like phenotype, including expression of granzyme B (121, 122) and IFN-γ (123, 124). These cells, upon bystander activation, can eliminate cells infected with noncognate virus and promote quick pathogen control but may promote tissue damage in the presence of a nonrelated chronic infection. The ability of memory CD8+ T cells to engage bystander inflammatory signals increases with additional Ag stimulations but decreases with time after the last Ag encounter (125). This parallels the acquisition of an effector-like phenotype in secondary and tertiary memory CD8+ T cells (126) as well as in mice exposed to pathogen normalization via cohousing with pet store counterparts (127). This contrasts with the progressive enrichment of quiescent Tcm in the absence of serial Ag stimulation. Interestingly, memory CD8+ T cell bystander activation does not happen only in response to systemic inflammation but also occurs in a localized way in response to immunizations (128). The presence of bystander inflammation (e.g., type I IFN) can also promote memory CD8+ T cell proliferation (129), although this seems limited if compared with Ag-driven proliferation (129). Localized bystander inflammation, moreover, can promote the accumulation of Trm quickly after inflammation onset (130). This suggests that inflammation can alter the intraorgan trafficking of memory CD8+ T cells. Also, cytokine-mediated recruitment of bystander circulating effector and memory CD8+ T cells is a hallmark of Ag-reactivated Trm (5153). This provides further evidence that bystander inflammation promotes differential migration of memory CD8+ T cells. Finally, inflammatory signals can also increase memory CD8+ T cell functional avidity (131). Overall, memory CD8+ T cells are equipped with sensing pathways that allow the recognition of bystander signals, allowing their response modulation.

The reactivation of memory CD8+ T cells may also be favored by inflammation associated with their cognate Ag. For example, the accumulation of acetate at sites of reinfection promotes glutaminolysis and cellular respiration, promoting enhanced memory CD8+ T cell function and subsequent pathogen clearance (132). A positive role of inflammation can also be found for gut Trm in response to Yersinia infection, in which prolonged production of IL-12 and type I IFN within Trm-rich immune clusters promote long-term Trm survival (133). These clusters are found in many nonlymphoid tissues, such as the brain (134), female reproductive tract (135), and lung (47). Therefore, a more detailed assessment is needed of whether the controlled production of inflammatory mediators in these sites can also favor Trm survival. These data once again illustrate a possible scenario in which controlled inflammation may be needed for the optimal survival and function of Trm.

Our field has made outstanding advancements to define how memory CD8+ T cells form, maintain, and act in response to multiple inflammatory environments. Despite these breakthroughs, many knowledge gaps remain, most of them discussed throughout this review. For instance, we now know that type 1 inflammatory signals can influence the quality and spatial distribution of CD8+ T cell priming, influencing their effector function and subsequent memory fate (76). However, not much is known about how type 2 stimuli influence CD8+ T cell memory. This may be particularly important for Trm, which can express type 2 cytokine receptors (136). Still, about the role of type 1 inflammation for CD8+ T cell responses, how does this pan out in the context of systemic inflammation, which induces a strong inflammatory monocyte response? Answering this question, and others, may give us a complete understanding of how different inflammatory responses control the CD8+ T cell memory fate.

Nevertheless, a common theme can be depicted about how inflammation affect memory CD8+ T cells. Regardless of the site or infection model for memory CD8+ T cell generation, maintenance, and secondary function, the presence of a controlled level of inflammatory signals may be ideal ((Fig. 1). If inflammation signals are absent or too low, they often result is a decay in memory generation and impaired reactivation. At the other end, exaggerated inflammatory signals typically divert CD8+ T cells toward terminal differentiation and death at an effector phase and impaired memory CD8+ T cell maintenance. Given that 1) there seems to be a common denominator for how inflammation affects all memory CD8+ T cell subsets and 2) inflammation often induces changes in the nature of existing memory CD8+ T cells (128), future studies aiming to understand how inflammation affects CD8+ T cell memory may benefit from limiting the subdivision in memory subsets. Obviously, the use of subsets to define memory CD8+ T cells is valuable because it is hard to understand general tendencies without placing these cells into defined groups. However, if we are considering multiple inflammatory backgrounds, subsets may not capture the complexity of the millions of clones generating a role for long-lived memory CD8+ T cells. This is especially true considering that memory cells resultant from one clone are not homogeneous, even when placed in the same subset.

FIGURE 1.

How inflammation can affect memory CD8+ T cells.

This hypothetical scheme highlights the common relation between inflammatory signals and memory CD8+ T cells. Independent of location or nature of memory CD8+ T cells, low or no inflammation mostly hinders memory CD8+ T cell generation (including the input of effector cells needed for effector-to-memory conversion) and survival. Conversely, excessive inflammation usually diverts activated CD8+ T cells toward terminal-like phenotypes, consequently leading to increased population death; this is also true for existing memory CD8+ T cells, in which too high levels of proinflammatory signals lead to both a conversion to a effector-like phenotype and increased attrition. There is a likely sweet spot, where enough type 1 inflammatory signals promote effective priming of CD8+ T cells (together with TCR and costimulation), appropriate MP generation (both in circulation and in tissues), and efficient maintenance and reactivation of memory CD8+ T cells, either in the presence or not of secondary Ag. Manipulations of local and/or systemic inflammation should ideally shape the inflammatory environment to reach this hypothetical sweet spot, which may vary from tissue to tissue and from infection to infection. The figure was created with Biorender.com.

FIGURE 1.

How inflammation can affect memory CD8+ T cells.

This hypothetical scheme highlights the common relation between inflammatory signals and memory CD8+ T cells. Independent of location or nature of memory CD8+ T cells, low or no inflammation mostly hinders memory CD8+ T cell generation (including the input of effector cells needed for effector-to-memory conversion) and survival. Conversely, excessive inflammation usually diverts activated CD8+ T cells toward terminal-like phenotypes, consequently leading to increased population death; this is also true for existing memory CD8+ T cells, in which too high levels of proinflammatory signals lead to both a conversion to a effector-like phenotype and increased attrition. There is a likely sweet spot, where enough type 1 inflammatory signals promote effective priming of CD8+ T cells (together with TCR and costimulation), appropriate MP generation (both in circulation and in tissues), and efficient maintenance and reactivation of memory CD8+ T cells, either in the presence or not of secondary Ag. Manipulations of local and/or systemic inflammation should ideally shape the inflammatory environment to reach this hypothetical sweet spot, which may vary from tissue to tissue and from infection to infection. The figure was created with Biorender.com.

Close modal

I thank I.C. Santiago for reading and review of the manuscript.

This work was supported by the National Institutes of Health, National Institute of Allergy and Infectious Diseases (R00-AI139381).

Abbreviations used in this article:

     
  • DC

    dendritic cell

  •  
  • KLRG1

    killer cell lectin-like receptor G 1

  •  
  • LCMV

    lymphocytic choriomeningitis virus

  •  
  • LLEC

    long-lived effector cell

  •  
  • MP

    memory precursor

  •  
  • Tcm

    central memory CD8+ T cell

  •  
  • TE

    terminal effector

  •  
  • Tem

    effector memory CD8+ T cell

  •  
  • Trm

    tissue-resident memory CD8+ T cell

  •  
  • Tscm

    stem cell–like memory CD8+ T cell

1.
Farber
D. L.
,
M. G.
Netea
,
A.
Radbruch
,
K.
Rajewsky
,
R. M.
Zinkernagel
.
2016
.
Immunological memory: lessons from the past and a look to the future.
Nat. Rev. Immunol.
16
:
124
128
.
2.
Williams
M. A.
,
M. J.
Bevan
.
2007
.
Effector and memory CTL differentiation.
Annu. Rev. Immunol.
25
:
171
192
.
3.
Solouki
S.
,
W.
Huang
,
J.
Elmore
,
C.
Limper
,
F.
Huang
,
A.
August
.
2020
.
TCR signal strength and antigen affinity regulate CD8+ memory T cells.
J. Immunol.
205
:
1217
1227
.
4.
Woodland
D. L.
2004
.
Jump-starting the immune system: prime-boosting comes of age.
Trends Immunol.
25
:
98
104
.
5.
Speiser
D. E.
,
D. T.
Utzschneider
,
S. G.
Oberle
,
C.
Münz
,
P.
Romero
,
D.
Zehn
.
2014
.
T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?
Nat. Rev. Immunol.
14
:
768
774
.
6.
Chang
J. T.
,
E. J.
Wherry
,
A. W.
Goldrath
.
2014
.
Molecular regulation of effector and memory T cell differentiation.
Nat. Immunol.
15
:
1104
1115
.
7.
Tscharke
D. C.
,
N. P.
Croft
,
P. C.
Doherty
,
N. L.
La Gruta
.
2015
.
Sizing up the key determinants of the CD8(+) T cell response.
Nat. Rev. Immunol.
15
:
705
716
.
8.
Huster
K. M.
,
V.
Busch
,
M.
Schiemann
,
K.
Linkemann
,
K. M.
Kerksiek
,
H.
Wagner
,
D. H.
Busch
.
2004
.
Selective expression of IL-7 receptor on memory T cells identifies early CD40L-dependent generation of distinct CD8+ memory T cell subsets.
Proc. Natl. Acad. Sci. USA
101
:
5610
5615
.
9.
Chi
H.
2012
.
Regulation and function of mTOR signalling in T cell fate decisions.
Nat. Rev. Immunol.
12
:
325
338
.
10.
Li
C.
,
B.
Zhu
,
Y. M.
Son
,
Z.
Wang
,
L.
Jiang
,
M.
Xiang
,
Z.
Ye
,
K. E.
Beckermann
,
Y.
Wu
,
J. W.
Jenkins
, et al
2019
.
The transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8+ T cell fitness and functionality. [Published erratum appears in 2020 Immunity 52: 201–202.]
Immunity
51
:
491
507.e7
.
11.
Laidlaw
B. J.
,
N.
Zhang
,
H. D.
Marshall
,
M. M.
Staron
,
T.
Guan
,
Y.
Hu
,
L. S.
Cauley
,
J.
Craft
,
S. M.
Kaech
.
2014
.
CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection.
Immunity
41
:
633
645
.
12.
Nguyen
T. H.
,
J. L.
McAuley
,
Y.
Kim
,
M. Z.
Zheng
,
N. A.
Gherardin
,
D. I.
Godfrey
,
D. F.
Purcell
,
L. C.
Sullivan
,
G. P.
Westall
,
P. C.
Reading
, et al
2021
.
Influenza, but not SARS-CoV-2, infection induces a rapid interferon response that wanes with age and diminished tissue-resident memory CD8+ T cells.
Clin. Transl. Immunology
10
:
e1242
.
13.
Mackay
L. K.
,
E.
Wynne-Jones
,
D.
Freestone
,
D. G.
Pellicci
,
L. A.
Mielke
,
D. M.
Newman
,
A.
Braun
,
F.
Masson
,
A.
Kallies
,
G. T.
Belz
,
F. R.
Carbone
.
2015
.
T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate.
Immunity
43
:
1101
1111
.
14.
Bromley
S. K.
,
H.
Akbaba
,
V.
Mani
,
R.
Mora-Buch
,
A. Y.
Chasse
,
A.
Sama
,
A. D.
Luster
.
2020
.
CD49a regulates cutaneous resident memory CD8+ T cell persistence and response.
Cell Rep.
32
:
108085
.
15.
Breton
G.
,
P.
Mendoza
,
T.
Hägglöf
,
T. Y.
Oliveira
,
D.
Schaefer-Babajew
,
C.
Gaebler
,
M.
Turroja
,
A.
Hurley
,
M.
Caskey
,
M. C.
Nussenzweig
.
2021
.
Persistent cellular immunity to SARS-CoV-2 infection.
J. Exp. Med.
218
:
20202515
.
16.
Merad
M.
,
J. C.
Martin
.
2020
.
Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. [Published erratum appears in 2020 Nat. Rev. Immunol. 20: 448.]
Nat. Rev. Immunol.
20
:
355
362
.
17.
Tay
M. Z.
,
C. M.
Poh
,
L.
Rénia
,
P. A.
MacAry
,
L. F. P.
Ng
.
2020
.
The trinity of COVID-19: immunity, inflammation and intervention.
Nat. Rev. Immunol.
20
:
363
374
.
18.
Buck
M. D.
,
D.
O’Sullivan
,
E. L.
Pearce
.
2015
.
T cell metabolism drives immunity.
J. Exp. Med.
212
:
1345
1360
.
19.
Chang
C. H.
,
J. D.
Curtis
,
L. B.
Maggi
Jr.
,
B.
Faubert
,
A. V.
Villarino
,
D.
O’Sullivan
,
S. C.
Huang
,
G. J.
van der Windt
,
J.
Blagih
,
J.
Qiu
, et al
2013
.
Posttranscriptional control of T cell effector function by aerobic glycolysis.
Cell
153
:
1239
1251
.
20.
Butz
E. A.
,
M. J.
Bevan
.
1998
.
Massive expansion of antigen-specific CD8+ T cells during an acute virus infection.
Immunity
8
:
167
175
.
21.
Kalia
V.
,
S.
Sarkar
,
S.
Subramaniam
,
W. N.
Haining
,
K. A.
Smith
,
R.
Ahmed
.
2010
.
Prolonged interleukin-2Ralpha expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo.
Immunity
32
:
91
103
.
22.
Kaech
S. M.
,
J. T.
Tan
,
E. J.
Wherry
,
B. T.
Konieczny
,
C. D.
Surh
,
R.
Ahmed
.
2003
.
Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.
Nat. Immunol.
4
:
1191
1198
.
23.
Joshi
N. S.
,
W.
Cui
,
A.
Chandele
,
H. K.
Lee
,
D. R.
Urso
,
J.
Hagman
,
L.
Gapin
,
S. M.
Kaech
.
2007
.
Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor.
Immunity
27
:
281
295
.
24.
Rutishauser
R. L.
,
G. A.
Martins
,
S.
Kalachikov
,
A.
Chandele
,
I. A.
Parish
,
E.
Meffre
,
J.
Jacob
,
K.
Calame
,
S. M.
Kaech
.
2009
.
Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties.
Immunity
31
:
296
308
.
25.
Omilusik
K. D.
,
J. A.
Best
,
B.
Yu
,
S.
Goossens
,
A.
Weidemann
,
J. V.
Nguyen
,
E.
Seuntjens
,
A.
Stryjewska
,
C.
Zweier
,
R.
Roychoudhuri
, et al
2015
.
Transcriptional repressor ZEB2 promotes terminal differentiation of CD8+ effector and memory T cell populations during infection.
J. Exp. Med.
212
:
2027
2039
.
26.
Zhou
X.
,
H. H.
Xue
.
2012
.
Cutting edge: generation of memory precursors and functional memory CD8+ T cells depends on T cell factor-1 and lymphoid enhancer-binding factor-1.
J. Immunol.
189
:
2722
2726
.
27.
Jeannet
G.
,
C.
Boudousquié
,
N.
Gardiol
,
J.
Kang
,
J.
Huelsken
,
W.
Held
.
2010
.
Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory.
Proc. Natl. Acad. Sci. USA
107
:
9777
9782
.
28.
Liu
Z.
,
Y.
Guo
,
S.
Tang
,
L.
Zhou
,
C.
Huang
,
Y.
Cao
,
H.
Huang
,
X.
Wu
,
D.
Meng
,
L.
Ye
, et al
2019
.
Cutting edge: transcription factor BCL6 is required for the generation, but not maintenance, of memory CD8+ T cells in acute viral infection.
J. Immunol.
203
:
323
327
.
29.
Wherry
E. J.
,
J. N.
Blattman
,
K.
Murali-Krishna
,
R.
van der Most
,
R.
Ahmed
.
2003
.
Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment.
J. Virol.
77
:
4911
4927
.
30.
Mackay
L. K.
,
A.
Rahimpour
,
J. Z.
Ma
,
N.
Collins
,
A. T.
Stock
,
M. L.
Hafon
,
J.
Vega-Ramos
,
P.
Lauzurica
,
S. N.
Mueller
,
T.
Stefanovic
, et al
2013
.
The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin.
Nat. Immunol.
14
:
1294
1301
.
31.
Jameson
S. C.
,
D.
Masopust
.
2018
.
Understanding subset diversity in T cell memory.
Immunity
48
:
214
226
.
32.
Jameson
S. C.
2021
.
The naming of memory T-cell subsets.
Cold Spring Harb. Perspect. Biol.
13
:
a037788
.
33.
Sallusto
F.
,
D.
Lenig
,
R.
Förster
,
M.
Lipp
,
A.
Lanzavecchia
.
1999
.
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.
Nature
401
:
708
712
.
34.
Weninger
W.
,
M. A.
Crowley
,
N.
Manjunath
,
U. H.
von Andrian
.
2001
.
Migratory properties of naive, effector, and memory CD8(+) T cells.
J. Exp. Med.
194
:
953
966
.
35.
Wherry
E. J.
,
V.
Teichgräber
,
T. C.
Becker
,
D.
Masopust
,
S. M.
Kaech
,
R.
Antia
,
U. H.
von Andrian
,
R.
Ahmed
.
2003
.
Lineage relationship and protective immunity of memory CD8 T cell subsets.
Nat. Immunol.
4
:
225
234
.
36.
Gattinoni
L.
,
D. E.
Speiser
,
M.
Lichterfeld
,
C.
Bonini
.
2017
.
T memory stem cells in health and disease.
Nat. Med.
23
:
18
27
.
37.
Gerlach
C.
,
E. A.
Moseman
,
S. M.
Loughhead
,
D.
Alvarez
,
A. J.
Zwijnenburg
,
L.
Waanders
,
R.
Garg
,
J. C.
de la Torre
,
U. H.
von Andrian
.
2016
.
The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis.
Immunity
45
:
1270
1284
.
38.
Olson
J. A.
,
C.
McDonald-Hyman
,
S. C.
Jameson
,
S. E.
Hamilton
.
2013
.
Effector-like CD8+ T cells in the memory population mediate potent protective immunity.
Immunity
38
:
1250
1260
.
39.
Omilusik
K. D.
,
M. S.
Nadjsombati
,
L. A.
Shaw
,
B.
Yu
,
J. J.
Milner
,
A. W.
Goldrath
.
2018
.
Sustained Id2 regulation of E proteins is required for terminal differentiation of effector CD8+ T cells.
J. Exp. Med.
215
:
773
783
.
40.
Sato
N.
,
H. J.
Patel
,
T. A.
Waldmann
,
Y.
Tagaya
.
2007
.
The IL-15/IL-15Ralpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells.
Proc. Natl. Acad. Sci. USA
104
:
588
593
.
41.
Valbon
S. F.
,
S. A.
Condotta
,
M. J.
Richer
.
2016
.
Regulation of effector and memory CD8(+) T cell function by inflammatory cytokines.
Cytokine
82
:
16
23
.
42.
Kondo
M.
,
K.
Akashi
,
J.
Domen
,
K.
Sugamura
,
I. L.
Weissman
.
1997
.
Bcl-2 rescues T lymphopoiesis, but not B or NK cell development, in common gamma chain-deficient mice.
Immunity
7
:
155
162
.
43.
Maraskovsky
E.
,
L. A.
O’Reilly
,
M.
Teepe
,
L. M.
Corcoran
,
J. J.
Peschon
,
A.
Strasser
.
1997
.
Bcl-2 can rescue T lymphocyte development in interleukin-7 receptor-deficient mice but not in mutant rag-1-/- mice.
Cell
89
:
1011
1019
.
44.
Cui
G.
,
M. M.
Staron
,
S. M.
Gray
,
P. C.
Ho
,
R. A.
Amezquita
,
J.
Wu
,
S. M.
Kaech
.
2015
.
IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity.
Cell
161
:
750
761
.
45.
Masopust
D.
,
V.
Vezys
,
A. L.
Marzo
,
L.
Lefrançois
.
2001
.
Preferential localization of effector memory cells in nonlymphoid tissue.
Science
291
:
2413
2417
.
46.
Gebhardt
T.
,
P. G.
Whitney
,
A.
Zaid
,
L. K.
Mackay
,
A. G.
Brooks
,
W. R.
Heath
,
F. R.
Carbone
,
S. N.
Mueller
.
2011
.
Different patterns of peripheral migration by memory CD4+ and CD8+ T cells.
Nature
477
:
216
219
.
47.
Anderson
K. G.
,
K.
Mayer-Barber
,
H.
Sung
,
L.
Beura
,
B. R.
James
,
J. J.
Taylor
,
L.
Qunaj
,
T. S.
Griffith
,
V.
Vezys
,
D. L.
Barber
,
D.
Masopust
.
2014
.
Intravascular staining for discrimination of vascular and tissue leukocytes.
Nat. Protoc.
9
:
209
222
.
48.
Schenkel
J. M.
,
K. A.
Fraser
,
V.
Vezys
,
D.
Masopust
.
2013
.
Sensing and alarm function of resident memory CD8+ T cells. [Published erratum appears in 2013 Nat. Immunol. 14: 876.]
Nat. Immunol.
14
:
509
513
.
49.
Fernandez-Ruiz
D.
,
W. Y.
Ng
,
L. E.
Holz
,
J. Z.
Ma
,
A.
Zaid
,
Y. C.
Wong
,
L. S.
Lau
,
V.
Mollard
,
A.
Cozijnsen
,
N.
Collins
, et al
2016
.
Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection. [Published erratum appears in 2019 Immunity 51: 780.]
Immunity
45
:
889
902
.
50.
Gebhardt
T.
,
L. M.
Wakim
,
L.
Eidsmo
,
P. C.
Reading
,
W. R.
Heath
,
F. R.
Carbone
.
2009
.
Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus.
Nat. Immunol.
10
:
524
530
.
51.
Ariotti
S.
,
M. A.
Hogenbirk
,
F. E.
Dijkgraaf
,
L. L.
Visser
,
M. E.
Hoekstra
,
J. Y.
Song
,
H.
Jacobs
,
J. B.
Haanen
,
T. N.
Schumacher
.
2014
.
T cell memory. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert.
Science
346
:
101
105
.
52.
Schenkel
J. M.
,
K. A.
Fraser
,
L. K.
Beura
,
K. E.
Pauken
,
V.
Vezys
,
D.
Masopust
.
2014
.
T cell memory. Resident memory CD8 T cells trigger protective innate and adaptive immune responses.
Science
346
:
98
101
.
53.
Ariotti
S.
,
J. B.
Beltman
,
R.
Borsje
,
M. E.
Hoekstra
,
W. P.
Halford
,
J. B.
Haanen
,
R. J.
de Boer
,
T. N.
Schumacher
.
2015
.
Subtle CXCR3-dependent chemotaxis of CTLs within infected tissue allows efficient target localization.
J. Immunol.
195
:
5285
5295
.
54.
Steinert
E. M.
,
J. M.
Schenkel
,
K. A.
Fraser
,
L. K.
Beura
,
L. S.
Manlove
,
B. Z.
Igyártó
,
P. J.
Southern
,
D.
Masopust
.
2015
.
Quantifying memory CD8 T cells reveals regionalization of immunosurveillance.
Cell
161
:
737
749
.
55.
Beura
L. K.
,
S.
Wijeyesinghe
,
E. A.
Thompson
,
M. G.
Macchietto
,
P. C.
Rosato
,
M. J.
Pierson
,
J. M.
Schenkel
,
J. S.
Mitchell
,
V.
Vezys
,
B. T.
Fife
, et al
2018
.
T Cells in nonlymphoid tissues give rise to lymph-node-resident memory T cells.
Immunity
48
:
327
338.e5
.
56.
Stark
R.
,
T. H.
Wesselink
,
F. M.
Behr
,
N. A. M.
Kragten
,
R.
Arens
,
F.
Koch-Nolte
,
K. P. J. M.
van Gisbergen
,
R. A. W.
van Lier
.
2018
.
T RM maintenance is regulated by tissue damage via P2RX7.
Sci. Immunol.
3
:
eaau1022
.
57.
Mani
V.
,
S. K.
Bromley
,
T.
Äijö
,
R.
Mora-Buch
,
E.
Carrizosa
,
R. D.
Warner
,
M.
Hamze
,
D. R.
Sen
,
A. Y.
Chasse
,
A.
Lorant
, et al
2019
.
Migratory DCs activate TGF-β to precondition naïve CD8+ T cells for tissue-resident memory fate.
Science
366
:
eaav5728
.
58.
Zhang
N.
,
M. J.
Bevan
.
2013
.
Transforming growth factor-β signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention.
Immunity
39
:
687
696
.
59.
Borges da Silva
H.
,
C.
Peng
,
H.
Wang
,
K. M.
Wanhainen
,
C.
Ma
,
S.
Lopez
,
A.
Khoruts
,
N.
Zhang
,
S. C.
Jameson
.
2020
.
Sensing of ATP via the purinergic receptor P2RX7 promotes CD8+ Trm cell generation by enhancing their sensitivity to the cytokine TGF-β.
Immunity
53
:
158
171.e6
.
60.
Shin
H.
,
A.
Iwasaki
.
2012
.
A vaccine strategy that protects against genital herpes by establishing local memory T cells.
Nature
491
:
463
467
.
61.
Bergsbaken
T.
,
M. J.
Bevan
.
2015
.
Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8+ T cells responding to infection.
Nat. Immunol.
16
:
406
414
.
62.
Caminschi
I.
,
M. H.
Lahoud
,
A.
Pizzolla
,
L. M.
Wakim
.
2019
.
Zymosan by-passes the requirement for pulmonary antigen encounter in lung tissue-resident memory CD8+ T cell development.
Mucosal Immunol.
12
:
403
412
.
63.
Slütter
B.
,
N.
Van Braeckel-Budimir
,
G.
Abboud
,
S. M.
Varga
,
S.
Salek-Ardakani
,
J. T.
Harty
.
2017
.
Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity.
Sci. Immunol.
2
:
eaag2031
.
64.
Schenkel
J. M.
,
K. A.
Fraser
,
K. A.
Casey
,
L. K.
Beura
,
K. E.
Pauken
,
V.
Vezys
,
D.
Masopust
.
2016
.
IL-15-independent maintenance of tissue-resident and boosted effector memory CD8 T cells.
J. Immunol.
196
:
3920
3926
.
65.
Merad
M.
,
P.
Sathe
,
J.
Helft
,
J.
Miller
,
A.
Mortha
.
2013
.
The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting.
Annu. Rev. Immunol.
31
:
563
604
.
66.
Heath
W. R.
,
F. R.
Carbone
.
2009
.
Dendritic cell subsets in primary and secondary T cell responses at body surfaces.
Nat. Immunol.
10
:
1237
1244
.
67.
Villadangos
J. A.
,
P.
Schnorrer
.
2007
.
Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo.
Nat. Rev. Immunol.
7
:
543
555
.
68.
Worbs
T.
,
S. I.
Hammerschmidt
,
R.
Förster
.
2017
.
Dendritic cell migration in health and disease.
Nat. Rev. Immunol.
17
:
30
48
.
69.
Gerner
M. Y.
,
W.
Kastenmuller
,
I.
Ifrim
,
J.
Kabat
,
R. N.
Germain
.
2012
.
Histo-cytometry: a method for highly multiplex quantitative tissue imaging analysis applied to dendritic cell subset microanatomy in lymph nodes.
Immunity
37
:
364
376
.
70.
Eisenbarth
S. C.
2019
.
Dendritic cell subsets in T cell programming: location dictates function.
Nat. Rev. Immunol.
19
:
89
103
.
71.
Stoltzfus
C. R.
,
J.
Filipek
,
B. H.
Gern
,
B. E.
Olin
,
J. M.
Leal
,
Y.
Wu
,
M. R.
Lyons-Cohen
,
J. Y.
Huang
,
C. L.
Paz-Stoltzfus
,
C. R.
Plumlee
, et al
2020
.
CytoMAP: a spatial analysis toolbox reveals features of myeloid cell organization in lymphoid tissues.
Cell Rep.
31
:
107523
.
72.
Brewitz
A.
,
S.
Eickhoff
,
S.
Dähling
,
T.
Quast
,
S.
Bedoui
,
R. A.
Kroczek
,
C.
Kurts
,
N.
Garbi
,
W.
Barchet
,
M.
Iannacone
, et al
2017
.
CD8+ T cells orchestrate pDC-XCR1+ dendritic cell spatial and functional cooperativity to optimize priming.
Immunity
46
:
205
219
.
73.
Woodruff
M. C.
,
B. A.
Heesters
,
C. N.
Herndon
,
J. R.
Groom
,
P. G.
Thomas
,
A. D.
Luster
,
S. J.
Turley
,
M. C.
Carroll
.
2014
.
Trans-nodal migration of resident dendritic cells into medullary interfollicular regions initiates immunity to influenza vaccine.
J. Exp. Med.
211
:
1611
1621
.
74.
Fransen
M. F.
,
M. J.
van Stipdonk
,
M.
Sluijter
,
S. P.
Schoenberger
,
C. J.
Melief
,
R.
Offringa
.
2010
.
Separate roles for antigen recognition and lymph node inflammation in CD8+ memory T cell formation.
J. Immunol.
185
:
3167
3173
.
75.
Curtsinger
J. M.
,
M. F.
Mescher
.
2010
.
Inflammatory cytokines as a third signal for T cell activation.
Curr. Opin. Immunol.
22
:
333
340
.
76.
Leal
J. M.
,
J. Y.
Huang
,
K.
Kohli
,
C.
Stoltzfus
,
M. R.
Lyons-Cohen
,
B. E.
Olin
,
M.
Gale
Jr.
,
M. Y.
Gerner
.
2021
.
Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation.
Sci. Immunol.
6
:
eabb9435
.
77.
Nakano
H.
,
K. L.
Lin
,
M.
Yanagita
,
C.
Charbonneau
,
D. N.
Cook
,
T.
Kakiuchi
,
M. D.
Gunn
.
2009
.
Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses.
Nat. Immunol.
10
:
394
402
.
78.
Jakubzick
C. V.
,
G. J.
Randolph
,
P. M.
Henson
.
2017
.
Monocyte differentiation and antigen-presenting functions.
Nat. Rev. Immunol.
17
:
349
362
.
79.
Zhou
X.
,
S.
Yu
,
D. M.
Zhao
,
J. T.
Harty
,
V. P.
Badovinac
,
H. H.
Xue
.
2010
.
Differentiation and persistence of memory CD8(+) T cells depend on T cell factor 1.
Immunity
33
:
229
240
.
80.
Zehn
D.
,
S.
Roepke
,
K.
Weakly
,
M. J.
Bevan
,
M.
Prlic
.
2014
.
Inflammation and TCR signal strength determine the breadth of the T cell response in a bim-dependent manner.
J. Immunol.
192
:
200
205
.
81.
Pham
N. L.
,
V. P.
Badovinac
,
J. T.
Harty
.
2009
.
A default pathway of memory CD8 T cell differentiation after dendritic cell immunization is deflected by encounter with inflammatory cytokines during antigen-driven proliferation.
J. Immunol.
183
:
2337
2348
.
82.
Cui
W.
,
N. S.
Joshi
,
A.
Jiang
,
S. M.
Kaech
.
2009
.
Effects of signal 3 during CD8 T cell priming: bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation.
Vaccine
27
:
2177
2187
.
83.
Obar
J. J.
,
L.
Lefrançois
.
2010
.
Early events governing memory CD8+ T-cell differentiation.
Int. Immunol.
22
:
619
625
.
84.
Aichele
P.
,
H.
Unsoeld
,
M.
Koschella
,
O.
Schweier
,
U.
Kalinke
,
S.
Vucikuja
.
2006
.
CD8 T cells specific for lymphocytic choriomeningitis virus require type I IFN receptor for clonal expansion.
J. Immunol.
176
:
4525
4529
.
85.
Kolumam
G. A.
,
S.
Thomas
,
L. J.
Thompson
,
J.
Sprent
,
K.
Murali-Krishna
.
2005
.
Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection.
J. Exp. Med.
202
:
637
650
.
86.
Pearce
E. L.
,
H.
Shen
.
2007
.
Generation of CD8 T cell memory is regulated by IL-12.
J. Immunol.
179
:
2074
2081
.
87.
von Andrian
U. H.
,
C. R.
Mackay
.
2000
.
T-cell function and migration. Two sides of the same coin.
N. Engl. J. Med.
343
:
1020
1034
.
88.
Hickman
H. D.
,
G. V.
Reynoso
,
B. F.
Ngudiankama
,
S. S.
Cush
,
J.
Gibbs
,
J. R.
Bennink
,
J. W.
Yewdell
.
2015
.
CXCR3 chemokine receptor enables local CD8(+) T cell migration for the destruction of virus-infected cells.
Immunity
42
:
524
537
.
89.
Plumlee
C. R.
,
B. S.
Sheridan
,
B. B.
Cicek
,
L.
Lefrançois
.
2013
.
Environmental cues dictate the fate of individual CD8+ T cells responding to infection.
Immunity
39
:
347
356
.
90.
Peng
Y.
,
A. J.
Mentzer
,
G.
Liu
,
X.
Yao
,
Z.
Yin
,
D.
Dong
,
W.
Dejnirattisai
,
T.
Rostron
,
P.
Supasa
,
C.
Liu
, et al
ISARIC4C Investigators
.
2020
.
Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19.
Nat. Immunol.
21
:
1336
1345
.
91.
Kared
H.
,
A. D.
Redd
,
E. M.
Bloch
,
T. S.
Bonny
,
H.
Sumatoh
,
F.
Kairi
,
D.
Carbajo
,
B.
Abel
,
E. W.
Newell
,
M. P.
Bettinotti
, et al
2021
.
SARS-CoV-2-specific CD8+ T cell responses in convalescent COVID-19 individuals.
J. Clin. Invest.
131
:
e145476
.
92.
Pipkin
M. E.
,
J. A.
Sacks
,
F.
Cruz-Guilloty
,
M. G.
Lichtenheld
,
M. J.
Bevan
,
A.
Rao
.
2010
.
Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells.
Immunity
32
:
79
90
.
93.
Stelekati
E.
,
H.
Shin
,
T. A.
Doering
,
D. V.
Dolfi
,
C. G.
Ziegler
,
D. P.
Beiting
,
L.
Dawson
,
J.
Liboon
,
D.
Wolski
,
M. A.
Ali
, et al
2014
.
Bystander chronic infection negatively impacts development of CD8(+) T cell memory.
Immunity
40
:
801
813
.
94.
Kilgore
A. M.
,
N. D.
Pennock
,
R. M.
Kedl
.
2020
.
cDC1 IL-27p28 production predicts vaccine-elicited CD8+ T cell memory and protective immunity.
J. Immunol.
204
:
510
517
.
95.
Borges da Silva
H.
,
L. K.
Beura
,
H.
Wang
,
E. A.
Hanse
,
R.
Gore
,
M. C.
Scott
,
D. A.
Walsh
,
K. E.
Block
,
R.
Fonseca
,
Y.
Yan
, et al
2018
.
The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells.
Nature
559
:
264
268
.
96.
Wanhainen
K. M.
,
S. C.
Jameson
,
H. B.
da Silva
.
2019
.
Self-regulation of memory CD8 T cell metabolism through extracellular ATP signaling.
Immunometabolism
1
:
e190009
97.
Murthy
A. M. V.
,
N.
Robinson
,
S.
Kumar
.
2020
.
Crosstalk between cGAS-STING signaling and cell death.
Cell Death Differ.
27
:
2989
3003
.
98.
Li
W.
,
L.
Lu
,
J.
Lu
,
X.
Wang
,
C.
Yang
,
J.
Jin
,
L.
Wu
,
X.
Hong
,
F.
Li
,
D.
Cao
, et al
2020
.
cGAS-STING-mediated DNA sensing maintains CD8+ T cell stemness and promotes antitumor T cell therapy.
Sci. Transl. Med.
12
:
eaay9013
.
99.
Johnnidis
J. B.
,
Y.
Muroyama
,
S. F.
Ngiow
,
Z.
Chen
,
S.
Manne
,
Z.
Cai
,
S.
Song
,
J. M.
Platt
,
J. M.
Schenkel
,
M.
Abdel-Hakeem
, et al
2021
.
Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage.
Sci. Immunol.
6
:
eabe3702
.
100.
Geva-Zatorsky
N.
,
E.
Sefik
,
L.
Kua
,
L.
Pasman
,
T. G.
Tan
,
A.
Ortiz-Lopez
,
T. B.
Yanortsang
,
L.
Yang
,
R.
Jupp
,
D.
Mathis
, et al
2017
.
Mining the human gut microbiota for immunomodulatory organisms.
Cell
168
:
928
943.e11
.
101.
Tanoue
T.
,
S.
Morita
,
D. R.
Plichta
,
A. N.
Skelly
,
W.
Suda
,
Y.
Sugiura
,
S.
Narushima
,
H.
Vlamakis
,
I.
Motoo
,
K.
Sugita
, et al
2019
.
A defined commensal consortium elicits CD8 T cells and anti-cancer immunity.
Nature
565
:
600
605
.
102.
Becattini
S.
,
E. R.
Littmann
,
R.
Seok
,
L.
Amoretti
,
E.
Fontana
,
R.
Wright
,
M.
Gjonbalaj
,
I. M.
Leiner
,
G.
Plitas
,
T. M.
Hohl
,
E. G.
Pamer
.
2020
.
Enhancing mucosal immunity by transient microbiota depletion.
Nat. Commun.
11
:
4475
.
103.
Arpaia
N.
,
C.
Campbell
,
X.
Fan
,
S.
Dikiy
,
J.
van der Veeken
,
P.
deRoos
,
H.
Liu
,
J. R.
Cross
,
K.
Pfeffer
,
P. J.
Coffer
,
A. Y.
Rudensky
.
2013
.
Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation.
Nature
504
:
451
455
.
104.
Ferreira
C.
,
L.
Barros
,
M.
Baptista
,
B.
Blankenhaus
,
A.
Barros
,
P.
Figueiredo-Campos
,
Š.
Konjar
,
A.
Lainé
,
N.
Kamenjarin
,
A.
Stojanovic
, et al
2020
.
Type 1 Treg cells promote the generation of CD8+ tissue-resident memory T cells.
Nat. Immunol.
21
:
766
776
.
105.
Graham
J. B.
,
A.
Da Costa
,
J. M.
Lund
.
2014
.
Regulatory T cells shape the resident memory T cell response to virus infection in the tissues.
J. Immunol.
192
:
683
690
.
106.
Condotta
S. A.
,
S. H.
Khan
,
D.
Rai
,
T. S.
Griffith
,
V. P.
Badovinac
.
2015
.
Polymicrobial sepsis increases susceptibility to chronic viral infection and exacerbates CD8+ T cell exhaustion.
J. Immunol.
195
:
116
125
.
107.
Beltra
J. C.
,
S.
Manne
,
M. S.
Abdel-Hakeem
,
M.
Kurachi
,
J. R.
Giles
,
Z.
Chen
,
V.
Casella
,
S. F.
Ngiow
,
O.
Khan
,
Y. J.
Huang
, et al
2020
.
Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms.
Immunity
52
:
825
841.e8
.
108.
Braun
J.
,
L.
Loyal
,
M.
Frentsch
,
D.
Wendisch
,
P.
Georg
,
F.
Kurth
,
S.
Hippenstiel
,
M.
Dingeldey
,
B.
Kruse
,
F.
Fauchere
, et al
2020
.
SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19.
Nature
587
:
270
274
.
109.
Grifoni
A.
,
D.
Weiskopf
,
S. I.
Ramirez
,
J.
Mateus
,
J. M.
Dan
,
C. R.
Moderbacher
,
S. A.
Rawlings
,
A.
Sutherland
,
L.
Premkumar
,
R. S.
Jadi
, et al
2020
.
Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals.
Cell
181
:
1489
1501.e15
.
110.
Le Bert
N.
,
A. T.
Tan
,
K.
Kunasegaran
,
C. Y. L.
Tham
,
M.
Hafezi
,
A.
Chia
,
M. H. Y.
Chng
,
M.
Lin
,
N.
Tan
,
M.
Linster
, et al
2020
.
SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.
Nature
584
:
457
462
.
111.
Sekine
T.
,
A.
Perez-Potti
,
O.
Rivera-Ballesteros
,
K.
Strålin
,
J. B.
Gorin
,
A.
Olsson
,
S.
Llewellyn-Lacey
,
H.
Kamal
,
G.
Bogdanovic
,
S.
Muschiol
, et al
Karolinska COVID-19 Study Group
.
2020
.
Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19.
Cell
183
:
158
168.e14
.
112.
Minervina
A. A.
,
E. A.
Komech
,
A.
Titov
,
M.
Bensouda Koraichi
,
E.
Rosati
,
I. Z.
Mamedov
,
A.
Franke
,
G. A.
Efimov
,
D. M.
Chudakov
,
T.
Mora
, et al
2021
.
Longitudinal high-throughput TCR repertoire profiling reveals the dynamics of T-cell memory formation after mild COVID-19 infection.
eLife
10
:
e63502
.
113.
Szabo
P. A.
,
P.
Dogra
,
J. I.
Gray
,
S. B.
Wells
,
T. J.
Connors
,
S. P.
Weisberg
,
I.
Krupska
,
R.
Matsumoto
,
M. M. L.
Poon
,
E.
Idzikowski
, et al
2021
.
Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19.
Immunity
54
:
797
814
114.
Xie
J.
,
C. W.
Chen
,
Y.
Sun
,
S. J.
Laurie
,
W.
Zhang
,
S.
Otani
,
G. S.
Martin
,
C. M.
Coopersmith
,
M. L.
Ford
.
2019
.
Increased attrition of memory T cells during sepsis requires 2B4.
JCI Insight
4
:
e126030
.
115.
Ebina-Shibuya
R.
,
E. E.
West
,
R.
Spolski
,
P.
Li
,
J.
Oh
,
M.
Kazemian
,
D.
Gromer
,
P.
Swanson
,
N.
Du
,
D. B.
McGavern
,
W. J.
Leonard
.
2021
.
Thymic stromal lymphopoietin limits primary and recall CD8+ T-cell anti-viral responses.
eLife
10
:
e61912
.
116.
Olesin
E.
,
R.
Nayar
,
P.
Saikumar-Lakshmi
,
L. J.
Berg
.
2018
.
The transcription factor Runx2 is required for long-term persistence of antiviral CD8+ memory T cells.
Immunohorizons
2
:
251
261
.
117.
Du
N.
,
H.
Kwon
,
P.
Li
,
E. E.
West
,
J.
Oh
,
W.
Liao
,
Z.
Yu
,
M.
Ren
,
W. J.
Leonard
.
2014
.
EGR2 is critical for peripheral naïve T-cell differentiation and the T-cell response to influenza.
Proc. Natl. Acad. Sci. USA
111
:
16484
16489
.
118.
van der Windt
G. J.
,
B.
Everts
,
C. H.
Chang
,
J. D.
Curtis
,
T. C.
Freitas
,
E.
Amiel
,
E. J.
Pearce
,
E. L.
Pearce
.
2012
.
Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development.
Immunity
36
:
68
78
.
119.
Chang
C. H.
,
J.
Qiu
,
D.
O’Sullivan
,
M. D.
Buck
,
T.
Noguchi
,
J. D.
Curtis
,
Q.
Chen
,
M.
Gindin
,
M. M.
Gubin
,
G. J.
van der Windt
, et al
2015
.
Metabolic competition in the tumor microenvironment is a driver of cancer progression.
Cell
162
:
1229
1241
.
120.
Colgan
S. P.
,
E. L.
Campbell
,
D. J.
Kominsky
.
2016
.
Hypoxia and mucosal inflammation.
Annu. Rev. Pathol.
11
:
77
100
.
121.
Kohlmeier
J. E.
,
T.
Cookenham
,
A. D.
Roberts
,
S. C.
Miller
,
D. L.
Woodland
.
2010
.
Type I interferons regulate cytolytic activity of memory CD8(+) T cells in the lung airways during respiratory virus challenge.
Immunity
33
:
96
105
.
122.
Chu
T.
,
A. J.
Tyznik
,
S.
Roepke
,
A. M.
Berkley
,
A.
Woodward-Davis
,
L.
Pattacini
,
M. J.
Bevan
,
D.
Zehn
,
M.
Prlic
.
2013
.
Bystander-activated memory CD8 T cells control early pathogen load in an innate-like, NKG2D-dependent manner.
Cell Rep.
3
:
701
708
.
123.
Berg
R. E.
,
E.
Crossley
,
S.
Murray
,
J.
Forman
.
2003
.
Memory CD8+ T cells provide innate immune protection against Listeria monocytogenes in the absence of cognate antigen.
J. Exp. Med.
198
:
1583
1593
.
124.
Soudja
S. M.
,
C.
Chandrabos
,
E.
Yakob
,
M.
Veenstra
,
D.
Palliser
,
G.
Lauvau
.
2014
.
Memory-T-cell-derived interferon-γ instructs potent innate cell activation for protective immunity.
Immunity
40
:
974
988
.
125.
Martin
M. D.
,
Q.
Shan
,
H. H.
Xue
,
V. P.
Badovinac
.
2017
.
Time and antigen-stimulation history influence memory CD8 T cell bystander responses.
Front. Immunol.
8
:
634
.
126.
Fraser
K. A.
,
J. M.
Schenkel
,
S. C.
Jameson
,
V.
Vezys
,
D.
Masopust
.
2013
.
Preexisting high frequencies of memory CD8+ T cells favor rapid memory differentiation and preservation of proliferative potential upon boosting.
Immunity
39
:
171
183
.
127.
Beura
L. K.
,
S. E.
Hamilton
,
K.
Bi
,
J. M.
Schenkel
,
O. A.
Odumade
,
K. A.
Casey
,
E. A.
Thompson
,
K. A.
Fraser
,
P. C.
Rosato
,
A.
Filali-Mouhim
, et al
2016
.
Normalizing the environment recapitulates adult human immune traits in laboratory mice.
Nature
532
:
512
516
.
128.
Maurice
N. J.
,
M. J.
McElrath
,
E.
Andersen-Nissen
,
N.
Frahm
,
M.
Prlic
.
2019
.
CXCR3 enables recruitment and site-specific bystander activation of memory CD8+ T cells.
Nat. Commun.
10
:
4987
.
129.
Tough
D. F.
,
P.
Borrow
,
J.
Sprent
.
1996
.
Induction of bystander T cell proliferation by viruses and type I interferon in vivo.
Science
272
:
1947
1950
.
130.
Ge
C.
,
I. R.
Monk
,
A.
Pizzolla
,
N.
Wang
,
J. G.
Bedford
,
T. P.
Stinear
,
G. P.
Westall
,
L. M.
Wakim
.
2019
.
Bystander activation of pulmonary Trm cells attenuates the severity of bacterial pneumonia by enhancing neutrophil recruitment.
Cell Rep.
29
:
4236
4244.e3
.
131.
Richer
M. J.
,
J. C.
Nolz
,
J. T.
Harty
.
2013
.
Pathogen-specific inflammatory milieux tune the antigen sensitivity of CD8(+) T cells by enhancing T cell receptor signaling.
Immunity
38
:
140
152
.
132.
Balmer
M. L.
,
E. H.
Ma
,
A. J.
Thompson
,
R.
Epple
,
G.
Unterstab
,
J.
Lötscher
,
P.
Dehio
,
C. M.
Schürch
,
J. D.
Warncke
,
G.
Perrin
, et al
2020
.
Memory CD8+ T cells balance pro- and anti-inflammatory activity by reprogramming cellular acetate handling at sites of infection.
Cell Metab.
32
:
457
467.e5
.
133.
Bergsbaken
T.
,
M. J.
Bevan
,
P. J.
Fink
.
2017
.
Local inflammatory cues regulate differentiation and persistence of CD8+ tissue-resident memory T cells.
Cell Rep.
19
:
114
124
.
134.
Wakim
L. M.
,
A.
Woodward-Davis
,
M. J.
Bevan
.
2010
.
Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence.
Proc. Natl. Acad. Sci. USA
107
:
17872
17879
.
135.
Iijima
N.
,
A.
Iwasaki
.
2014
.
T cell memory. A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells.
Science
346
:
93
98
.
136.
Milner
J. J.
,
C.
Toma
,
B.
Yu
,
K.
Zhang
,
K.
Omilusik
,
A. T.
Phan
,
D.
Wang
,
A. J.
Getzler
,
T.
Nguyen
,
S.
Crotty
, et al
2017
.
Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. [Published erratum appears in 2018 Nature 554: 392.]
Nature
552
:
253
257
.

The author has no financial conflicts of interest.

This article is distributed under the terms of the CC BY-NC-ND 4.0 Unported license.