SARM1 regulates the survival and effector function of Th1 and Th17 cells

The biology of T lymphocytes is directly regulated by cellular metabolism, and high levels of NAD are required to sustain the elevated glycolytic activity observed in T cells transitioning from a quiescent state. In this study, we investigated how SARM1, an enzyme with NAD hydrolase activity, impacts T-cell function. We found that colitis induced by the adoptive transfer of naive CD4+ T cells into Rag−/− mice was more severe when Sarm1^−/− cells were transferred. These cells exhibited a modest increase in IFN-γ production and a reduction in IL-17 production. In vitro, Th1 differentiation was enhanced in Sarm1^−/− cells, whereas Th17 differentiation was reduced. The same phenotype was observed in Rag1^-/- mice reconstituted with WT or Sarm1^−/− naive CD4+ T cells (50:50). We identified a greater number of Sarm1^−/− cells compared with WT cells after 30 days of transfer, although no differences in T-cell activation or proliferation were observed.  To further investigate the role of SARM1 in T-cell survival and IFN-γ production, we overexpressed Sarm1 in Th1 cells. Surprisingly, all cells transduced with the Sarm1 overexpression plasmid died, whereas cells transduced with the empty vector remained viable. We then activated CD4+ T cells in vitro in the presence of a potent SARM1 activator and observed a dramatic reduction in both cell viability and IFN-γ production compared with vehicle-treated cells. Finaly, We also investigated the impact of SARM1 deficiency in experimental autoimmune colitis and found that mice receiving Sarm1^−/− CD4+ T cells developed markedly more severe colitis compared with mice receiving WT cells. Collectively, our data suggests that SARM1 may play an important role in regulating the effector function of CD4+ T cells and may also contribute to their contraction following activation.