TLR9 limits mouse and human B cell responses

Abstract

Abstract TLR9 can augment B cell activation, but also prevents autoimmune pathogenesis through an unknown mechanism. Herein we describe a cell-intrinsic mechanism that limits the extent of B cell activation by TLR9 ligands delivered by the B cell antigen receptor. This self-limiting response requires that TLR agonists be linked with B cell receptor ligands, as it is not observed with independent B cell receptor and TLR9 ligation. The underlying mechanism involves p38 dependent G1 cell cycle arrest that precedes intrinsic mitochondrial apoptosis, and is shared by all pre-immune murine B cell subsets and CD27− human B cells. B cells can be rescued from this death mechanism by survival or inflammatory cytokines, and preferentially switch to IgG2c producing cells both in vitro and in vivo. These findings reveal a previously unappreciated system of crosstalk that limits responses to antigens containing TLR9 ligands, and suggest that circumventing this response-limiting process can promote sustained autoantibody production.