This special issue is the second in the series of small collections of topical reviews in The Journal of Immunology and features a collection of three Brief Reviews on innate/innate-like lymphocytes: “Life In-Between: Bridging Innate and Adaptive Immunity” (1–3).
By virtue of multicellularity and on being birthed into a microbial world, metazoan life is confronted by two challenges: one caused by internal and the other by external stressors. A major internal stressor is the replicative autonomy of each cell with which comes the propensity to accumulate mutations, some tumorigenic, as the cell ages. Other internal stressors include noxious cellular metabolic by-products such as organic crystals that incite sterile inflammation. External stressors are those inflicted by microbes, including both pathogenic ones and those with which the host gets into a symbiotic habit (4). In the continual surrounds of internal and external stressors, the growing complexities of metazoan life-forms necessitated the evolution of a specialized physiologic system—the immune system. The immune system, as a constituent of the 10 bodily systems, evolved to sense perturbations in the milieu intérieur (homeostasis) and to actuate an appropriate response that matches the nature of the stressors to return to a set homeostatic state. Containment and removal of the stressor, which are essential to the initiation of tissue repair, are accomplished initially by the more archaic, multimodular innate immune system. Should innate mechanisms fail to contain and clear the inciter, the evolutionarily younger, adaptive immune system made up of lymphocytes is recruited to assist in the healing process. The quick-acting innate system, elements of which arose in early metazoans, senses an altered homeostatic state via pattern recognition receptors. By contrast, the slow-acting, adaptive immune system, which arose in vertebrates, senses alterations in homeostasis by means of clonally expressed Ag-specific BCRs (and Abs) and TCRs. In addition to these conventional lymphocytes, the vertebrate immune system contains subsets of lymphocytes that do not neatly fit the innate versus adaptive paradigm. These are collectively called unconventional lymphocytes, which in this editorial I call innate/innate-like lymphocytes.
The protagonists of this collection of reviews are multitudinous. Much has been written about innate/innate-like lymphocytes over the last few decades, but only recently have attempts been made to synthesize this literature in the context of an integrated immune system (5–9). Such a synthesis requires taking stock of our current understanding of the functions, development, and evolution of innate/innate-like lymphocytes. These three areas make up the small collection of brief reviews in this special issue. In a Herculean task, the opening review by Van Kaer et al. (1) elegantly distills down the vast literature to plainly describe the salient features of all currently known innate/innate-like lymphocytes. These include innate-like B and T cells—B-1 and marginal zone B cells, NKT cells, mucosal-associated invariant T (MAIT) cells, γδ T cells, H-2M3–restricted T cells, H-2Qa1/HLA-E–restricted T cells, and CD8αα intraepithelial T lymphocytes, as well as innate non-B and non-T lymphocytes—NK cells, innate lymphoid cells (ILCs), and lymphoid tissue inducer cells. These diverse cell types in the immune system are strung together by several common features: 1) all are of lymphoid origin, exhibit autoreactivity, and express surface markers typical of conventional memory B and T lymphocytes but do not retain long-term memories of previous encounters with pathogens; 2) they strategically congregate at secondary lymphoid and/or nonlymphoid tissues, especially at barrier sites in close vicinity of the microbial consortium; 3) their development and/or maturation is linked to microbial products from this consortium; 4) a subset of innate-like lymphocytes expresses rearranged BCRs or TCRs, both αβ and γδ, which show an innate mode of ligand recognition; 5) activating ligands of innate-like lymphocytes include self and/or microbial peptides, N-formylated mitochondrial/microbial peptides, intact proteins, lipids, and metabolites; 6) the functions of innate-like T lymphocytes are controlled by nonclassical MHC class I–like molecules, such as H-2M3, H-2Qa1/HLA-E, MR-1 (MHC-related 1), as well as group I and II CD1 molecules, or by a combination of inflammatory cytokines alone, e.g., type I IFNs or IL-12 and IL-18; 7) innate/innate-like lymphocytes act quickly, almost as rapidly as innate immune cells; and 8) the effector functions of several innate/innate-like lymphocytes mirror type I, II, and III immunity. These features of innate/innate-like lymphocytes allow them to integrate sensory signals from the innate immune system and relay this context to downstream innate and adaptive immune responses. Hence, innate/innate-like lymphocytes bridge innate and adaptive immunity (9).
Effector functions are ingrained in innate/innate-like lymphocytes during development. Hence, Morgan and Kee (2) describe genomic and transcriptional control of innate-like T lymphocyte development and function, focusing on the semi-invariant NKT cells, wherein ontogenetic and effector differentiation mechanisms have been defined in significant molecular detail. In developing immune cells, cell fate decisions and cell identity are governed by chromatin landscapes and hierarchical transcriptional networks, which are collectively called the genome-regulatory circuits/networks, that act on lineage-restricted precursors. Thus, the decision to be (or not to be) a T cell is made within lymphoid-primed multipotent precursors and/or the common/clonogenic lymphoid precursor by the action of the core apex transcription factors NOTCH, T cell factor-1 (Tcf7-encoded TCF1), GATA3, and E2A (Tcf3 encoded) and its regulator, Id2 (inhibitor of DNA binding 2). NOTCH1 effectors TCF1 and E2A control Tcf12 expression to code for HEB, and in turn, HEB regulates expression of the Rag genes and thus the rearrangement of TCR gene segments including those that code for the invariant TCR α-chains of the semi-invariant NKT and MAIT cells. Conversely, Id2, induced by NFIL3 (NF, IL-3 regulated), in combination with TOX (thymocyte selection–associated high-mobility group box) downregulates Tcf3, muting the core NOTCH1-TCF1 T cell apex transcription factors to steer development down the innate lymphoid lineage (5, 10).
ILCs and the innate-like T lymphocytes that express a semi-invariant TCR, including a subset of γδ T cells, differentiate into type I (cellular immunity: cytotoxicity, IFN-γ, and TNF), type II (humoral immunity: IL-4, IL-5, IL-9, and IL-13), and type III (barrier immunity: IL-17 and IL-22) effector subsets similar to conventional T cells (11). But, unlike conventional T cells, which undergo effector differentiation in the periphery on Ag encounter, effector differentiation in innate-like T lymphocytes occurs in the thymus itself shortly after positive selection. Hence a unique transcriptional program makes developing innate-like T lymphocytes permissive to tissue cues—agonistic ligand/s and costimulatory, homotypic SLAM (signaling lymphocyte activation molecule) interactions—for effector differentiation. Effector differentiation can continue in the periphery, again driven by agonistic interactions with self-ligands or metabolic products derived from symbiotic microbes. Upon fate commitment, induction of the transcription factor PLZF (promyelocytic leukemia zinc finger encoded by Zbtb16) in innate-like T cell precursors downstream of persistent and high-affinity TCR signaling and in ILC precursors is essential for both development and effector differentiation. How Zbtb16 is regulated in each cell subset and the downstream events that beget type I, II, and III effectors are covered in significant detail by Morgan and Kee (2).
Last, as a group, innate/innate-like lymphocytes display redundant functions. Reasons for this redundancy remain unknown. One approach to fill this gap is to penetrate the evolutionary origins of innate/innate-like lymphocytes; Harly and colleagues' review (3) does exactly that. Comparative genomics of lineage-specific soluble mediators—Ifng, Il4, Il17, Il22, and Il23—and transcription factors—Eomes, Foxp3, Rorc, Tbx21, and Zbtb16—trace their origins to >500 million years ago, appearing perhaps during the Cambrian explosion in the Paleozoic era (5, 12). Large granular and nongranular lymphocytes that lack variable lymphocyte receptors were reported in the jawless vertebrate (lamprey), suggesting that mammalian NK cells (large granular cells)—the natural cytotoxic ILC and ILC2 (nongranular cells)—originated at the dawn of vertebrate evolution in the Mesozoic era. ILC1s and ILC3s appear to have evolved later (13). Among the innate-like T lymphocytes, γδ T cells exhibit similar deep origin as they are reported in lampreys and other vertebrate lineages. Curiously, however, squamates have lost TRG and TRD gene segments and hence are the only known group that lacks γδ T cells (14). Evolutionary implications of this loss are unknown. By contrast with the γδ T cell origin, NKT and MAIT cells appeared as eutherian (placental mammals) innovations. Certain eutherian species lack semi-invariant NKT and MAIT cells. In some of them, an analogous cell type, which expresses an invariant TRAV41-TRAJ38 TCR α-chain that appears to have coevolved with an MHC class I–like MHX molecule, has been reported (15). In light of this discovery, Harly et al. (3) argue that the evolutionary origins of the semi-invariant NKT and MAIT cells may lie in amphibians, which have evolved XNC10-restricted Vα6- and XNC4-restricted Vα45-invariant T cells (3, 9). Understanding the genome-regulatory networks in these novel innate-like T lymphocytes will shed light onto the relatedness of these lineages to each other. Thus, although “it is plainly denied to finite understandings to ascend to the very beginning, and to comprehend the nature of the operation of the First Cause of anything…[T]he ablest endeavours here to penetrate the beginning of things do but carry us, when most successful, a few steps nearer that beginning,” as prophesied by Sir Richard Owen (16). That notwithstanding, we have not yet approached an asymptote; hence much more awaits the curious mind.
In summary, innate/innate-like lymphocytes are multitudinous. Although they originate from common lymphocyte precursors, they diverge early and mature by mechanisms employing PLZF as a lineage-specifying transcription factor. Hence innate/innate-like lymphocytes are distinct from innate immune cells of myeloid lineage, as well as conventional B and T lymphocytes. They home to nonlymphoid, barrier tissues for border patrol. Innate/innate-like lymphocytes function at the edge (limbus in Latin) of the innate and adaptive immune systems and thereby appear to form a “limbic immune system.” In this proposal for a triune immune system, we make no assumption that the limbic immune system is an evolutionary transition between the innate and adaptive immune systems. Instead, the limbic immune system is a conglomeration of independently acting modules, arising at different times in evolution, in many instances repurposing loosely common genome-regulatory circuits to accomplish a common task: to integrate information relayed by the innate sensory immune system about the local tissue umwelt and to provide context to downstream effector innate and adaptive immune responses. The multiple modules add robustness and evolvability to this limbic system to keep abreast of the ever-changing environment and the quick-evolving microbial cosmos, especially of those members of an otherwise symbiont community that turn pathobiont without much notice!
I thank H.M.S. Algood, G.D. Okoye, and L. Van Kaer for comments on this piece, and the contributors, reviewers, and editors of the three Brief Reviews in this special issue.
This work was supported by Research Career Scientist Award IK6 BX004595.