NLRP6 regulates donor T cell activation and acute graft-versus-host disease via ZAP-70-Erk pathway.

NOD-like receptor family pyrin domain-containing 6 (Nlrp6) is an inflammasome related molecule expressed in intestinal epithelial and immune cells. While previous work showed that Nlrp6 in host nonhematopoietic cells exacerbates gastrointestinal acute graft-versus-host disease (aGVHD), its role in donor T cells remained unclear. Here we show that donor T cell-intrinsic Nlrp6 exerts a protective effect in murine aGVHD models. Mice receiving Nlrp6 deficient (Nlrp6-/-) donor T cells had reduced survival and more severe GVHD than those receiving wild-type T cells. Mechanistically, Nlrp6-/- T cells showed enhanced proliferation, preferential Th1 differentiation, and upregulation of Th1 cytokines. Enhanced phosphorylation of Zap-70 and Erk1/2 indicated hyperactivation of proximal TCR signaling. Despite increased aGVHD, graft-versus tumor (GVT) responses preserved in Nlrp6-/- T cells. Clinically, T cells from aGVHD patients showed decreased Nlrp6 expression, supporting the relevance of our findings. Collectively, these data suggest that Nlrp6 negatively regulates allogeneic donor T cell responses, via Zap-70-Erk1/2 signaling, while sparing anti-tumor immunity. We conclude that beneficial effects of Nlrp6 expression in donor T cells opposes the detrimental Nlrp6 effects in intestinal epithelial cells during aGVHD indicating Nlrp6 has cell type-specific and context-dependent antagonistic biological functions on controlling aGVHD inflammatory responses.