title: Adaptor protein DOK3 promotes plasma cell differentiation by regulating the expression of programmed cell death 1 ligands.
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.
authors: Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668;
authors: Xijun
authors: X
authors: Ou
authors: Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668;and Departments of Physiology.
authors: Shengli
authors: S
authors: Xu
authors: Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668;
authors: Yan-Feng
authors: YF
authors: Li
authors: 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.
authors: Kong-Peng
authors: KP
authors: Lam
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D060890:B7-H1 Antigen / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling; D002451:Cell Compartmentation; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D000939:Epitopes / Q000276:immunology; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D010950:Plasma Cells / Q000166:cytology* / Q000378:metabolism*; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060890:B7-H1 Antigen; C406768:Dok3 protein, mouse; D000939:Epitopes; D008024:Ligands; D061027:Programmed Cell Death 1 Ligand 2 Protein; D012333:RNA, Messenger