The autoimmunity-associated gene RGS1 affects the frequency of T follicular helper cells

RGS1 (regulator of G-protein signaling 1) has been associated with multiple autoimmune disorders including type 1 diabetes. RGS1 desensitizes the chemokine receptors CCR7 and CXCR4 that are critical to the localization of T and B cells in lymphoid organs. To explore how RGS1 variation contributes to autoimmunity, we generated Rgs1 knockdown (KD) mice in the nonobese diabetic (NOD) model for type 1 diabetes. We found that Rgs1 KD increased the size of germinal centers, but decreased the frequency of T follicular helper (T(FH)) cells. We show that loss of Rgs1 in T cells had both a T cell-intrinsic effect on migration and T(FH) cell frequency, and an indirect effect on B cell migration and germinal center formation. Notably, several recent publications described an increase in circulating T(FH) cells in patients with type 1 diabetes, suggesting this cell population is involved in pathogenesis. Though Rgs1 KD was insufficient to alter diabetes frequency in the NOD model, our findings raise the possibility that RGS1 plays a role in autoimmunity owing to its function in T(FH) cells. This mechanistic link, while speculative at this time, would lend support to the notion that T(FH) cells are key participants in autoimmunity and could explain RGS1’s association with several immune-mediated diseases.