title: B-cell-intrinsic function of TAPP adaptors in controlling germinal center responses and autoantibody production in mice.
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 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.
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Nipun
authors.initials: N
authors.lastname: Jayachandran
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Landego
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Sen
authors.initials: S
authors.lastname: Hou
authors.affiliation: College of Life Sciences, University of Dundee, Dundee, Scotland, UK.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Marshall
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000378:metabolism; D001323:Autoantibodies / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology*; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D018858:Germinal Center / Q000276:immunology*; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D058534:Class I Phosphatidylinositol 3-Kinases; D060889:Inducible T-Cell Co-Stimulator Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; C556694:Icos protein, mouse; C461495:Plekha1 protein, mouse; C461496:Plekha2 protein, mouse; C421683:Pik3cd protein, mouse
keywords: Antibodies; Autoimmunity; B cells; Cellular activation; Signal transduction