Abstract
Preprogrammed IL-17-producing γδ T cells constitute a poorly understood class of lymphocytes that express rearranged antigen receptors but appear to make little use of them. γδT17 cells were first characterized as tissue-resident sentinels with innate effector function. However, ongoing research continues to reveal unexpected complexity to this unusual subset, including phenotypic plasticity, memory-like activity and unique migratory behavior. Despite these advances, at the core of γδT17 cell biology remain fundamental gaps in knowledge: Are γδT17 cells truly innate or has the importance of the T cell receptor been overlooked? How unique are they among IL-17-producing lymphocytes? How similar are these cells between mice and humans? We speculate that answering these unresolved questions is key to successful manipulation of γδ T cells in clinical settings.
Highlights
Whereas conventional αβ T cells expressing diverse T cell receptors (TCRs) continuously patrol lymphoid tissues and extensively proliferate and differentiate to generate pathogen-tailored effector responses upon detection of cognate antigen, numerous innate-like lymphocyte subsets constitutively occupy barrier tissues and respond far more rapidly to tissue stress and infection. γδ T cells that produce interleukin 17 (IL-17, termed γδT17 or alternatively γδ17, Tγδ17) are one such population attracting increasing attention
While recent work has somewhat clarified the role of TCR signaling in γδT17 ontogeny, whether true ligand-driven selection, akin to that experienced by αβ T cells, occurs during their thymic development remains unclear
It is worth reiterating that γδT17 cell ontogeny requires RORγt and TGF-β, two factors crucial to de novo polarization of Th17 cells from naïve αβ T cells, suggesting that the induction of the Type 3 program in these cell types is fundamentally conserved despite occurring under different conditions, in different sites and with some divergent signal requirements [19, 20]
Summary
Whereas conventional αβ T cells expressing diverse T cell receptors (TCRs) continuously patrol lymphoid tissues and extensively proliferate and differentiate to generate pathogen-tailored effector responses upon detection of cognate antigen, numerous innate-like lymphocyte subsets constitutively occupy barrier tissues and respond far more rapidly to tissue stress and infection. γδ T cells that produce interleukin 17 (IL-17, termed γδT17 or alternatively γδ, Tγδ17) are one such population attracting increasing attention. Γδ T cell-derived IL-17 is critical for control of pathogen load during the earliest stages of infection in a range of models This innate-like response is not unique to γδT17 cells, as innate lymphoid cells (ILCs) and some invariant αβ T cell subsets contribute to early production of Type 3 cytokines, which include IL-17, IL-22 and granulocytemacrophage colony stimulating factor (GM-CSF). It is possible that the more tissue-biased Vγ6+ subset prioritizes immunosurveillance of barrier sites, while the lymphoid organ-skewed Vγ4+ subset serves as a pool that is mobilized to distal sites during local and systemic challenges, this remains to be formally demonstrated These two populations can respond to distinct stimuli even within the same location, as demonstrated by dermal Vγ4+ and Vγ6+ cells which selectively expand following skin colonization with Corynebacterium accolens and Staphylococcus epidermidis, respectively [14]. We review the current state of knowledge in these emerging concepts, in the form of the key questions that should be answered to progress knowledge of γδT17 cells toward clinical application
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