Unique and Common Features of Innate-Like Human Vδ2+ γδT Cells and Mucosal-Associated Invariant T Cells

Abstract

Mucosal-associated invariant T (MAIT) cells are innate-like T cells abundant in humans that can be activated in a TCR-independent manner by inflammatory and antiviral cytokines. In humans, the capacity for TCR-independent activation is functionally linked to a transcriptional program that can be identified by the expression of the C-type lectin receptor, CD161. In addition to MAIT cells, it has been demonstrated that a subset of γδT cells expresses CD161 and can be activated by TCR-independent cytokine stimulation. In this study, we sought to clarify the nature of cytokine-responsive human γδT cells. We could link CD161 expression on Vδ2+ versus Vδ1+ γδT cells to the observation that Vδ2+ γδT cells, but not Vδ1+ γδT cells, robustly produced IFN-γ upon stimulation with a variety of cytokine combinations. Interestingly, both CD161+ and CD161− Vδ2+ γδT cells responded to these stimuli, with increased functionality within the CD161+ subset. This innate-like responsiveness corresponded to high expression of PLZF and IL-18Rα, analogous to MAIT cells. Vδ2+ γδT cells in human duodenum and liver maintained a CD161+ IL-18Rα+ phenotype and produced IFN-γ in response to IL-12 and IL-18 stimulation. In contrast to MAIT cells, we could not detect IL-17A production but observed higher steady-state expression of Granzyme B by Vδ2+ γδT cells. Finally, we investigated the frequency and functionality of γδT cells in the context of chronic hepatitis C virus infection, as MAIT cells are reduced in frequency in this disease. By contrast, Vδ2+ γδT cells were maintained in frequency and displayed unimpaired IFN-γ production in response to cytokine stimulation. In sum, human Vδ2+ γδT cells are a functionally distinct population of cytokine-responsive innate-like T cells that is abundant in blood and tissues with similarities to human MAIT cells.

A fetal wave of human type-3 γδ T cells with restricted TCR diversity persists into adulthood

“…Such Vγ9Vδ2 + T cells still display a considerable TCR diversity, but collectively respond to the intracellular accumulation of microbial and tumor-derived metabolites called phosphoantigens 4 , which are somehow support binding of canonical Vγ9Vδ2 + T cells to butyrophilin-molecules BTN3A1 5 and BTN2A1 6,7 . Furthermore, Vγ9Vδ2 + T cells share common features with other human innate-like T cells like invariant natural killer T (NKT) and mucosa-associated invariant T (MAIT) cells, including expression of PLZF 8 . The remaining non-Vγ9Vδ2 + human γδ T cell subsets express diverse TRG rearrangements, preferentially paired with Vδ1 3 .…”

Neutrophils Suppress Mucosal-Associated Invariant T Cells

“…As previously reported, Vδ2 + T cells generally expressed higher levels of both granzyme B and perforin than MAIT cells. 23, 24, 25 IL-17A production was insubstantial both in the absence and presence of neutrophils in both cell types (Figure 2C).…”

Suppressive activity of Vδ2+ γδ T cells on αβ T cells is licensed by TCR signaling and correlates with signal strength

“…Since IL-15 and IL-12 alone or in combination enhanced the activation of PAg-stimulated γδ T cells [24,36,38] and TGF-β/IL-15 induced Foxp3 in Vδ2 + T cells, which then suppressed the proliferation of αβ T cells [21], TCR stimulation-where indicated-was combined with either one of these cytokines or combinations thereof. Untouched Vδ2 + T cells did not exhibit any inhibitory effect on the proliferation of anti-CD3/anti-CD28 stimulated αβ T cells, while TCR-bypass stimulation with IL-12/IL-18 [39] combined with IL-15 resulted in slight effects, this constituting only 16% of the inhibition mediated by TCR-crosslink-stimulated cells (average 68% suppression, Fig. 1a).…”