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

X Ou, S Xu, YF Li, KP Lam - Proceedings of the National …, 2014 - National Acad Sciences
X Ou, S Xu, YF Li, KP Lam
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
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 …
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.
National Acad Sciences