Unique and common Features of innate-like human Vdδ2+ γδT cells and Mucosal-associated invariant T cells

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 gamma delta T 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 gamma delta T cells. We could link CD161 expression on V delta 2(+) versus V delta 1(+) gamma delta T cells to the observation that V delta 2(+) gamma dT cells, but not V delta 1(+) gamma delta T cells, robustly produced IFN-gamma upon stimulation with a variety of cytokine combinations. Interestingly, both CD161(+) and CD161-V delta 2(+) gamma dT cells responded to these stimuli, with increased functionality within the CD161(+) subset. This innate-like responsiveness corresponded to high expression of PLZF and IL-18R alpha, analogous to MAIT cells. V delta 2(+) gamma delta T cells in human duodenum and liver maintained a CD161(+) IL-18R alpha(+) phenotype and produced IFN-gamma 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 V delta 2(+) gamma delta T cells. Finally, we investigated the frequency and functionality of gamma delta T cells in the context of chronic hepatitis C virus infection, as MAIT cells are reduced in frequency in this disease. By contrast, V delta 2(+) gamma delta T cells were maintained in frequency and displayed unimpaired IFN-gamma production in response to cytokine stimulation. In sum, human V delta 2(+) gamma delta T 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.