B cell-intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice

TY - JOUR

T1 - B cell-intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice

AU - Jayachandran, Nipun

AU - Landego, Ivan

AU - Hou, Sen

AU - Alessi, Dario R.

AU - Marshall, Aaron J.

N1 - This work was supported by the Canadian Institutes of Health Research (MOP-93771).

PY - 2017/2/10

Y1 - 2017/2/10

N2 - 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 bone marrow 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. This article is protected by copyright. All rights reserved.

AB - 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 bone marrow 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. This article is protected by copyright. All rights reserved.

U2 - 10.1002/eji.201646596

DO - 10.1002/eji.201646596

M3 - Article

C2 - 27859053

SN - 0014-2980

VL - 47

SP - 280

EP - 290

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 2

ER -