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

Nipun Jayachandran, Ivan Landego, Sen Hou, Dario R. Alessi, Aaron J. Marshall (Lead / Corresponding author)

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5 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)280-290
Number of pages11
JournalEuropean Journal of Immunology
Volume47
Issue number2
Early online date15 Nov 2016
DOIs
Publication statusPublished - 10 Feb 2017

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