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

Abstract

Protein kinase Cδ (PKCδ) 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 PKCδ deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of PKCδ in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that PKCδ is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that PKCδ 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 PKCδ 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, PKCδ deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation.

View publisher note:

Article of Significant Interest Selected from This Issue by the Editors

ACKNOWLEDGMENTS

This work was supported by NIH grants 1R03AR062783-01A1 (A.L.), P01 AI091580 (J.P.R.), K01CA113367 (J.P.R.), and R56-AI095292 (J.P.R.); an ARRA supplement (J.P.R.); the Sandler Program in Basic Science (J.P.R.); K08 AR059723 (J.Z.); a Rosalind Russell Medical Research Foundation Bechtel award (J.Z.); an Arthritis National Research Foundation grant (J.Z.); and the Howard Hughes Medical Institute (A.W.).

We thank Haopeng Wang and Marsilius Mues for help with tail vein injections and members of the Weiss and Roose laboratories for helpful discussions.

A.L. designed and did experiments, analyzed the data, and wrote the manuscript. J.Z. designed and did experiments, analyzed data, and revised the manuscript. T.L. provided technical assistance. M.L. generated the PKCδ^−/− mice. A.W. designed experiments, provided reagents and support, and revised the manuscript. J.P.R. designed experiments, supervised the research, revised the manuscript, and provided support.

We declare no competing financial interests.