| First Author | Cannons JL | Year | 2006 |
| Journal | J Exp Med | Volume | 203 |
| Issue | 6 | Pages | 1551-65 |
| PubMed ID | 16754717 | Mgi Jnum | J:124375 |
| Mgi Id | MGI:3721447 | Doi | 10.1084/jem.20052097 |
| Citation | Cannons JL, et al. (2006) SAP regulates T cell-mediated help for humoral immunity by a mechanism distinct from cytokine regulation. J Exp Med 203(6):1551-65 |
| abstractText | 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. |
