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Adaptor protein DOK3 promotes plasma cell differentiation by regulating the expression of programmed cell death 1 ligands.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 8/5/2014, Vol. 111 Issue 31, p11431-11436, 6p
- Publication Year :
- 2014
-
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<superscript>-/-</superscript> mice have increased populations of T follicular-helper (T<subscript>fh</subscript>) 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<superscript>-/-</superscript> 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<superscript>-/-</superscript> 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 PLCĪ³2 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- PLASMA cells
CELL death
IMMUNIZATION
ANTIGENS
CALCINEURIN
CYCLOSPORINE
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 111
- Issue :
- 31
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 97429617
- Full Text :
- https://doi.org/10.1073/pnas.1400539111