| First Author | Jayachandran N | Year | 2017 |
| Journal | Eur J Immunol | Volume | 47 |
| Issue | 2 | Pages | 280-290 |
| PubMed ID | 27859053 | Mgi Jnum | J:246248 |
| Mgi Id | MGI:5923481 | Doi | 10.1002/eji.201646596 |
| Citation | Jayachandran N, et al. (2017) B-cell-intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice. Eur J Immunol 47(2):280-290 |
| abstractText | 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. |
