SAP regulation of follicular helper CD4 T cell development and humoral immunity is independent of SLAM and Fyn kinase

Megan M. McCausland, Isharat Yusuf, Hung Tran, Nobuyuki Ono, Yusuke Yanagi, Shane Crotty

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)817-828
Number of pages12
JournalJournal of Immunology
Volume178
Issue number2
DOIs
Publication statusPublished - Jan 15 2007

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Humoral Immunity
Helper-Inducer T-Lymphocytes
Phosphotransferases
Germinal Center
T-Lymphocytes
Signaling Lymphocytic Activation Molecule Associated Protein
Lymphocytic choriomeningitis virus
Lymphoproliferative Disorders
Medical Genetics
Virus Diseases
Plasma Cells
Tail
Cell Differentiation
B-Lymphocytes
Phenotype
Mutation

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

SAP regulation of follicular helper CD4 T cell development and humoral immunity is independent of SLAM and Fyn kinase. / McCausland, Megan M.; Yusuf, Isharat; Tran, Hung; Ono, Nobuyuki; Yanagi, Yusuke; Crotty, Shane.

In: Journal of Immunology, Vol. 178, No. 2, 15.01.2007, p. 817-828.

Research output: Contribution to journalArticle

McCausland, Megan M. ; Yusuf, Isharat ; Tran, Hung ; Ono, Nobuyuki ; Yanagi, Yusuke ; Crotty, Shane. / SAP regulation of follicular helper CD4 T cell development and humoral immunity is independent of SLAM and Fyn kinase. In: Journal of Immunology. 2007 ; Vol. 178, No. 2. pp. 817-828.
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