B-cell-intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice
| Autor: | Nipun, Jayachandran, Ivan, Landego, Sen, Hou, Dario R, Alessi, Aaron J, Marshall |
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| Rok vydání: | 2016 |
| Předmět: |
Mice
Knockout B-Lymphocytes Class I Phosphatidylinositol 3-Kinases Intracellular Signaling Peptides and Proteins Membrane Proteins Germinal Center Lymphocyte Activation Inducible T-Cell Co-Stimulator Protein Mice Inbred C57BL Mice Phosphatidylinositol 3-Kinases Antibodies Antinuclear Animals Immunologic Memory Cells Cultured Autoantibodies |
| Zdroj: | European journal of immunology. 47(2) |
| ISSN: | 1521-4141 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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