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* Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
Department of Medical Biophysics and Immunology, Princess Margaret Hospital, Toronto, Canada; and
Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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.
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1 This work was supported in part by a Cancer Research Institute Investigator Award (to S.C.) and a Pew Scholar Award (to S.C.).
2 Address correspondence and reprint requests to Dr. Shane Crotty, Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92121. E-mail address: shane{at}liai.org
3 Abbreviations used in this paper: SAP, SLAM-associated protein; XLP, X-linked lymphoproliferative disease; ITSM, immunotyrosine switch motif; MHCII, MHC class II; LCMV, lymphocytic choriomeningitis virus; PNA, peanut lectin agglutinin; QPCR, quantitative real-time PCR; WT, wild type.
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