B-cell-intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice
| Autor: | Aaron J. Marshall, Ivan Landego, Dario R. Alessi, Sen Hou, Nipun Jayachandran |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Kinase Immunology Autoantibody Germinal center Biology medicine.disease_cause Molecular biology Autoimmunity 03 medical and health sciences 030104 developmental biology medicine.anatomical_structure Endocrinology Internal medicine medicine biology.protein Immunology and Allergy Signal transduction Antibody Protein kinase B B cell |
| Zdroj: | European Journal of Immunology. 47:280-290 |
| ISSN: | 0014-2980 |
| 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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