Adaptive γδ T cell function is subverted by Yersinia pseudotuberculosis outer proteins

Abstract

Abstract γδ T cells are an unconventional subset of multifunctional T cells enriched in mucosal barrier tissues. After foodborne Listeria monocytes (Lm) infection, an activated CD44hiCD27loVγ4 subset of γδ T cells formed in the mesenteric lymph nodes (MLN) that shared numerous characteristics with traditional T cells including anamnestic responses. While attempting to uncover the specificity of Lm-elicited memory cells utilizing heterologous challenge infections we observed that Lm-elicited γδ T cell function was induced with heat-killed Yersinia pseudotuberculosis (Yptb) but not live Yptb suggesting that Yptb employs immune evasion strategies to limit anti-pathogen adaptive γδ T cell functions. Live Yptb inhibited CD44hiCD27loVγ4 T cell IL-17A and IFNγ production integral for anti-pathogen immunity. Tracking Yptb translocation through a FRET-based reporter assay revealed preferential translocation of Yptb outer proteins (Yop) into adaptive γδ T cells over conventional T cells and an abrogated cytokine response compared to their non-translocated counterparts within the same environment. Using a series of Yptb mutants deficient in translocated effector proteins, we determined that YopH inhibited IL-17A production while YopJ inhibited IFNγ production. Inhibition of Stat4 phosphorylation in γδ T cells was observed in a translocation, YopJ, and IL-12/IL-23p40 dependent manner, suggesting that YopJ inhibits IFNγ production through Stat4 phosphorylation. Collectively, these data demonstrate direct inhibitory mechanisms of γδ T cell function mediated by the Yptb effectors YopH and YopJ and identify an unknown pathogenesis pathway utilized by Yptb to subvert immune function.