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Protein kinase Cδ promotes transitional B cell-negative selection and limits proximal B cell receptor signaling to enforce tolerance

  • Author(s): Limnander, A
  • Zikherman, J
  • Lau, T
  • Leitges, M
  • Weiss, A
  • Roose, JP
  • et al.

Published Web Location

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3993585/
No data is associated with this publication.
Abstract

Protein kinase Cδ (PKCδ) deficiency causes autoimmune pathology in humansand mice and is crucial for the maintenance of B cell homeostasis. However, the mechanisms underlying autoimmune disease in PKCδ deficiency remain poorly defined. Here, weaddress 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-activatingfactor (BAFF) receptor. Wefound 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. © 2014, American Society for Microbiology.

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