Failed Downregulation of PI3K Signaling Makes Autoreactive B Cells Receptive to Bystander T Cell Help

Abstract

Abstract The role of T cell help in autoantibody responses is not well understood. Because tolerance mechanisms govern both T and B cell responses, one might predict that both T cell tolerance and B cell tolerance must be defeated in autoantibody responses requiring T cell help. To define whether autoreactive B cells depend on T cells to generate autoantibody responses, we studied the role of T cells in murine autoantibody responses resulting from acute B cell–specific deletion of regulatory phosphatases. Ars/A1 B cells are DNA reactive and require continuous inhibitory signaling by the tyrosine phosphatase SHP-1 and the inositol phosphatases SHIP-1 and PTEN to maintain unresponsiveness. Acute B cell–restricted deletion of any of these phosphatases results in an autoantibody response. In this study, we show that CD40–CD40L interactions are required to support autoantibody responses of B cells whose anergy has been compromised. If the B cell–intrinsic driver of loss of tolerance is failed negative regulation of PI3K signaling, bystander T cells provide sufficient CD40-mediated signal 2 to support an autoantibody response. However, although autoantibody responses driven by acute B cell–targeted deletion of SHP-1 also require T cells, bystander T cell help does not suffice. These results demonstrate that upregulation of PI3K signaling in autoreactive B cells, recapitulating the effect of multiple autoimmunity risk alleles, promotes autoantibody responses both by increasing B cells’ cooperation with noncognate T cell help and by altering BCR signaling. Receptiveness to bystander T cell help enables autoreactive B cells to circumvent the fail-safe of T cell tolerance.