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Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11431-6. doi: 10.1073/pnas.1400539111. Epub 2014 Jul 22.

Adaptor protein DOK3 promotes plasma cell differentiation by regulating the expression of programmed cell death 1 ligands.

Author information

1
Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668;
2
Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668;and Departments of Physiology.
3
Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668;and Departments of Physiology,Microbiology, andPediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599 lam_kong_peng@bti.a-star.edu.sg.

Abstract

The adaptor Downstream-of-Kinase (DOK) 3 functions as a negative regulator and attenuates B-cell receptor-mediated calcium signaling. Although DOK3 is dispensable for early B-cell development, its role in plasma cell (PC) differentiation is unknown. Here, we show that Dok3(-/-) mice have increased populations of T follicular-helper (Tfh) and germinal center (GC) B cells upon immunization with a T-cell-dependent antigen. However, interestingly, they generate significantly fewer PCs. Bone marrow reconstitution experiments show that the PC defect is B-cell intrinsic and due to the inability of Dok3(-/-) B cells to sustain programmed cell death 1 (PD-1) ligand 1 (PDL1) and up-regulate PD-1 ligand 2 (PDL2) expressions that are critical for PC differentiation. Overexpression of PDL2 rectifies the PC differentiation defect in Dok3(-/-) B cells. We further demonstrate that calcium signaling suppresses the transcription of PD-1 ligands. Abrogation of calcium signaling in B cells by deleting BTK or PLCγ2 or inhibiting calcineurin with cyclosporine A leads to increased expression of PD-1 ligands. Thus, our study reveals DOK3 as a nonredundant regulator of PC differentiation by up-regulating PD-1 ligand expression through the attenuation of calcium signaling.

PMID:
25053811
PMCID:
PMC4128136
DOI:
10.1073/pnas.1400539111
[Indexed for MEDLINE]
Free PMC Article

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