期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 47, 期 2, 页码 280-290出版社
WILEY
DOI: 10.1002/eji.201646596
关键词
Antibodies; Autoimmunity; B cells; Cellular activation; Signal transduction
类别
资金
- Canadian Institutes of Health Research [MOP93771]
- MRC [MC_U127015387, MC_U127070193, MC_UU_12016/2, MC_EX_G0802532] Funding Source: UKRI
- Medical Research Council [MC_UU_12016/2, MC_U127015387, MC_U127070193, MC_EX_G0802532] Funding Source: researchfish
Control of B-cell signal transduction is critical to prevent production of pathological autoantibodies. Tandem PH domain containing proteins (TAPPs) specifically bind PI(3,4)P2, a phosphoinositide product generated by PI 3-kinases and the phosphatase SHIP. TAPP KI mice bearing PH domain-inactivating mutations in both TAPP1 and TAPP2 genes, uncoupling them from PI(3,4) P2, exhibit increased BCR-induced activation of the kinase Akt and develop lupus-like characteristics including anti-DNA antibodies and deposition of immune complexes in kidneys. Here, we find that TAPP KI mice develop chronic germinal centers (GCs) with age and show abnormal expression of B-cell activation and memory markers. Upon immunization with T-dependent Ag, TAPP KI mice develop functional but abnormally large GCs, associated with increased GC B-cell survival. Disruption of chronic GCs in TAPP KI mice by deletion of the costimulatory molecule ICOS abrogate anti-DNA and anti-nuclear antibody production in TAPP KI mice, indicating an essential role for GCs. Moreover, TAPP KI B cells are sufficient to drive chronic GC responses and recapitulate the autoimmune phenotype in BM chimeric mice. Our findings demonstrate a B-cell-intrinsic role of TAPP-PI(3,4) P2 interaction in regulating GC responses and autoantibody production and suggest that uncontrolled Akt activity in B cells can drive autoimmunity.
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