Protein Kinase Cδ Promotes Transitional B Cell-Negative Selection and Limits Proximal B Cell Receptor Signaling To Enforce Tolerance

Protein kinase C delta (PKC delta) deficiency causes autoimmune pathology in humans and mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKC delta deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKC delta in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKC delta is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKC delta is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca2+-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for PKC delta as a proximal negative regulator of BCR signaling that substantially impacts survival and proliferation of mature follicular B cells. As a consequence of these distinct roles, PKC delta deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation.