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

Significance Statement

The presented model illustrates the role of Protein kinase cδ  in B cell receptor (BCR) signaling at distinct stages of B cell development. Developing B cells exit the bone marrow and migrate to the spleen as transitional 1 (T1) B cells. T1 B cells are highly sensitive to antigen-induced apoptosis, a trait that allows self-reactive cells that encounter antigen to be clonally deleted from the B cell repertoire. T1 B cellsenter the spleen via the periarteriallymphoid sheath (PALS) andundergo an importantstep of negative selection, a process that is frequently disrupted in lupus patients. Our studies show that the kinase Protein kinase cδ  is required to activate a pro-apoptotic Ca2+-dependent pathway to Erk activation in bone marrow transitional B cells as well as splenic T1 B cells. PKCdthus couples BCR signaling to apoptosis at these developmental stages(1-3).

As T1 cells migrate from the PALS into the splenic follicle and become T2 cells their signaling properties change substantially. These B cells lose the ability to activate the Ca2+-Erk pathway, they are less sensitive to antigen-induced apoptosis and instead they tune their antigen responsiveness by downregulating surface IgM(BCR) levels in a manner proportional to antigen reactivity. We have shown that, in addition to facilitating negative selection of T1 B cells, Protein kinase cδ  acts as a negative regulator of BCR signaling throughout development and in mature B cells by at least two distinct mechanisms: 1- Protein kinase cδ  sets the threshold of antigenic signaling required for surface IgM downregulation, a key mechanism that dampens the responsiveness of anergic B cells; and 2- Protein kinase cδ  negatively regulates proximal BCR signaling. As a consequence of these roles, Protein kinase cδ  deficiency leads to an abnormally autoreactive B cell repertoire that is additionally hyperresponsive to antigen stimulation, leading to severeautoimmune pathology.

1.            Limnander A, Depeille P, Freedman TS, Liou J, Leitges M, Kurosaki T, et al. STIM1, Protein kinase cδ  and RasGRP set a threshold for proapoptotic Erk signaling during B cell development. Nature immunology. 2011;12(5):425-33. doi: 10.1038/ni.2016. PubMed PMID: 21441934; PubMed Central PMCID: PMC3623929.

2.            Limnander A, Weiss A. Ca-dependent Ras/Erk signaling mediates negative selection of autoreactive B cells. Small GTPases. 2011;2(5):282-8. doi: 10.4161/sgtp.2.5.17794. PubMed PMID: 22292132; PubMed Central PMCID: PMC3265820.

3.            Limnander A, Zikherman J, Lau T, Leitges M, Weiss A, Roose JP. Protein kinase cδ  promotes transitional B cell negative selection and limits proximal BCR signaling to enforce tolerance. Mol Cell Biol. 2014. doi: 10.1128/MCB.01699-13. PubMed PMID: 24515435.

 

 

Illustration below made by Anna Hupalowska.

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

Journal Reference

Limnander A, Zikherman J, Lau T, Leitges M, Weiss A, Roose JP.

Mol Cell Biol. 2014 Apr;34(8):1474-85.

Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.

  

Abstract

 PProtein kinase cδ  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 Protein kinase cδ  deficiency remain poorly defined. Here, we address the antigen-dependent and -independent roles of Protein kinase cδ  in B cell development, repertoire selection, and antigen responsiveness. We demonstrate that Protein kinase cδ  is rapidly phosphorylated downstream of both the B cell receptor (BCR) and the B cell-activating factor (BAFF) receptor. We found that Protein kinase cδ  is essential for antigen-dependent negative selection of splenic transitional B cells and is required for activation of the proapoptotic Ca(2+)-Erk pathway that is selectively activated during B cell-negative selection. Unexpectedly, we also identified a previously unrecognized role for Protein kinase cδ 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, Protein kinase cδ  deficiency leads to the survival and development of a B cell repertoire that is not only aberrantly autoreactive but also hyperresponsive to antigen stimulation.

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