title: SAP regulation of follicular helper CD4 T cell development and humoral immunity is independent of SLAM and Fyn kinase.
abstract: Mutations in SH2D1A resulting in lack of SLAM-associated protein (SAP) expression cause the human genetic immunodeficiency X-linked lymphoproliferative disease. A severe block in germinal center development and lack of long-term humoral immunity is one of the most prominent phenotypes of SAP(-) mice. We show, in this study, that the germinal center block is due to an essential requirement for SAP expression in Ag-specific CD4 T cells to develop appropriate follicular helper T cell functions. It is unknown what signaling molecules are involved in regulation of SAP-dependent CD4 T cell help functions. SAP binds to the cytoplasmic tail of SLAM, and we show that SLAM is expressed on resting and activated CD4 T cells, as well as germinal center B cells. In addition, SAP can recruit Fyn kinase to SLAM. We have now examined the role(s) of the SLAM-SAP-Fyn signaling axis in in vivo CD4 T cell function and germinal center development. We observed normal germinal center development, long-lived plasma cell development, and Ab responses in SLAM(-/-) mice after a viral infection (lymphocytic choriomeningitis virus). In a separate series of experiments, we show that SAP is absolutely required in CD4 T cells to drive germinal center development, and that requirement does not depend on SAP-Fyn interactions, because CD4 T cells expressing SAP R78A are capable of supporting normal germinal center development. Therefore, a distinct SAP signaling pathway regulates follicular helper CD4 T cell differentiation, separate from the SLAM-SAP-Fyn signaling pathway regulating Th1/Th2 differentiation.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92121, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: McCausland
authors.forename: Isharat
authors.initials: I
authors.lastname: Yusuf
authors.forename: Hung
authors.initials: H
authors.lastname: Tran
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ono
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yanagi
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D015704:CD4 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1