The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published online 5 June 2006 doi:10.1084/jem.20052097
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 6, 1551-1565
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ARTICLE

 SAP regulates T cell–mediated help for humoral immunity by a mechanism distinct from cytokine regulation

Jennifer L. Cannons1, Li J. Yu1, Dragana Jankovic2, Shane Crotty3, Reiko Horai1, Martha Kirby1, Stacie Anderson1, Allen W. Cheever2, Alan Sher2, and Pamela L. Schwartzberg1

1 National Human Genome Research Institute and 2 National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892
3 Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, San Diego, CA 92121

CORRESPONDENCE Pamela L. Schwartzberg: pams{at}mail.nih.gov

X-linked lymphoproliferative disease is caused by mutations affecting SH2D1A/SAP, an adaptor that recruits Fyn to signal lymphocyte activation molecule (SLAM)-related receptors. After infection, SLAM-associated protein (SAP)–/– mice show increased T cell activation and impaired humoral responses. Although SAP–/– mice can respond to T-independent immunization, we find impaired primary and secondary T-dependent responses, with defective B cell proliferation, germinal center formation, and antibody production. Nonetheless, transfer of wild-type but not SAP-deficient CD4 cells rescued humoral responses in reconstituted recombination activating gene 2–/– and SAP–/– mice. To investigate these T cell defects, we examined CD4 cell function in vitro and in vivo. Although SAP-deficient CD4 cells have impaired T cell receptor–mediated T helper (Th)2 cytokine production in vitro, we demonstrate that the humoral defects can be uncoupled from cytokine expression defects in vivo. Instead, SAP-deficient T cells exhibit decreased and delayed inducible costimulator (ICOS) induction and heightened CD40L expression. Notably, in contrast to Th2 cytokine defects, humoral responses, ICOS expression, and CD40L down-regulation were rescued by retroviral reconstitution with SAP-R78A, a SAP mutant that impairs Fyn binding. We further demonstrate a role for SLAM/SAP signaling in the regulation of early surface CD40L expression. Thus, SAP affects expression of key molecules required for T–B cell collaboration by mechanisms that are distinct from its role in cytokine regulation.

Abbreviations used: GC, germinal center; ICOS, inducible costimulator; LCMV, lymphocytic choriomeningitis virus; NP, 4-hydroxy-3-nitrophenylacetyl; PCC, pigeon cytochrome-c; PNA, peanut agglutinin; SAP, signal lymphocyte activation molecule–associated protein; SEA, schistosome egg antigen; SLAM, signal lymphocyte activation molecule; SRBC, sheep red blood cell; XLP, X-linked lymphoproliferative.


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