CD3^bright signals on γδ T cells identify IL‐17A‐producing Vγ6Vδ1⁺ T cells

Abstract

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto-immunity. γδ T cells are recognized as IL-17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3(bright) γδ T-cell subset with an effector memory phenotype to rapidly produce IL-17A, but not interferon-γ. CD3(bright) γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1(+) T-cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor-related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL-23 and NOD-like receptor family, pyrin domain containing 3 (NLRP3)-inflammasome-dependent IL-1β. Finally, we demonstrated that IL-17-producing CD3(bright) γδ T cells responded promptly and strongly to pneumococcal infection and during skin inflammation. Here, we propose a new way to specifically analyze IL-17-producing Vγ6/Vδ1(+) T cells based on the level of CD3 signals. Using this gating strategy, our data reinforce the crucial role of this γδ T-cell subset in respiratory and skin disorders.

Differential Responsiveness of Innate-like IL-17– and IFN-γ–Producing γδ T Cells to Homeostatic Cytokines

“…RORgt + gdT-17 cells express the highest levels of IL-7R and very low levels of IL-15Rb (Fig. 2), which is in agreement with previous reports (14,17,18). Interestingly, all three subsets express IL-7R to some degree, but only the innatelike gdT-IFNg cells express significant levels of IL-15Rb (Fig.…”

A clonotypic Vγ4Jγ1/Vδ5Dδ2Jδ1 innate γδ T-cell population restricted to the CCR6+CD27− subset

“…Thus, the canonical Vg4 þ Vd5 þ TCR classifies a hitherto unrecognized conserved subset of innate and presumably IL-17-producing Vg4 þ T cells. Notably, invariant Vg4 þ Vd5 þ T cells are actually abundant in peripheral lymphoid organs in the same magnitude as IL-17-producing Vg6 þ Vd1 þ cells 33,34 . In future studies, it will be interesting to compare the common and discrete functions of these two invariant gd T-cell subsets that are likely innate 'natural' IL-17A-producers.…”

“…Thus, with Vg4 þ T cells making up to 50% of all gd T cells derived from the pLN 32 , the actual rate of clonotypic invariant Vd5Dd2Jd1 þ gd T cells is 1.5-2% among all gd T cells. This remarkably high frequency is in the range of invariant IL-17A-producing Vg6Vd1 þ T cells that constitute 2-4% among all gd T cells in secondary lymphoid organs 33,34 . Nevertheless, only moderate expansion of this subset in peripheral tissues as compared with the thymus underlines their genuine innate nature.…”

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

“…Intriguingly, gut IL-17A mRNA was increased in experimental NEC in baboons (28), and recently IL-17A protein was shown to impair enterocyte tight junctions, increase enterocyte apoptosis, and reduce enterocyte proliferation leading to NEC in mice (29), highlighting the potential role of the IL-18/IL-17A axis in other neonatal inflammatory diseases. The deleterious role of excessive IL-17A, produced by many different cellular sources including a subset of γδT cells that can produce IL-17A rapidly via an IL-1R1-dependent pathway (30,31), is well established in the pathogenesis of severe inflammatory and ischemic-injury models, including sepsis (23,32,33). However, the connection we have shown between IL-18 and downstream IL-1R1-dependent IL-17A production in the setting of sepsis clarifies a significant prior gap in our knowledge and has identified another potential therapeutic avenue.…”