SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation.
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.
Cannons
Jennifer L
JL
National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
Yu
Li J
LJ
Jankovic
Dragana
D
Crotty
Shane
S
Horai
Reiko
R
Kirby
Martha
M
Anderson
Stacie
S
Cheever
Allen W
AW
Sher
Alan
A
Schwartzberg
Pamela L
PL
D000818:Animals; D000917:Antibody Formation; D015703:Antigens, CD; D016207:Cytokines / Q000276:immunology*; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D007136:Immunoglobulins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D013601:T-Lymphocytes / Q000276:immunology*; D014960:X Chromosome
D015703:Antigens, CD; D016207:Cytokines; D006023:Glycoproteins; D007136:Immunoglobulins; D011956:Receptors, Cell Surface; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1