Immunology SAP Orchestrates SLAM Signals

The activation of immune cells requires tight control of signaling. Signaling through the signaling lymphocyte activation molecule (SLAM) attenuates T cell stimulation, and mutation of the SLAM-associated protein (SAP) results in X-linked lymphoproliferative (XLP) disease. Latour et al. have identified some of the components required for SLAM signaling and have found that SAP mediates the formation of a protein complex on SLAM. SAP consists of little more than a single src homology 2 (SH2) domain, yet Latour et al. found that phosphotyrosine-independent binding of SAP to the plasma membrane-proximal Tyr²⁸⁸ of SLAM led to the recruitment of the protein tyrosine kinase FynT to SLAM. Tyr³¹⁵ and Tyr³³⁵ both underwent phosphorylation and recruited the adaptor proteins Shc, Dok1 and Dok2, the SH2 domain-containing inositol phosphatase (SHIP), and RasGAP. Activated SLAM, in the presence of SAP, blocked the secretion of the T helper cell type 1 (Th1) cytokine interferon- (IFN-), but not interleukin-2 from T cell receptor-stimulated T cells in vitro. Upon T cell activation, the amount of cellular SAP decreases, whereas the amount of SLAM increases slightly. Subsequently, the amount of SAP increases, which leads to decreased IFN- output. Thus, these results suggest that SLAM and SAP might act to fine-tune the profile of cytokines produced over the duration of the immune response.

S. Latour, G. Gish, C. D. Helgason, R. K. Humphries, T. Pawson, A. Veillette, Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene product. Nature Immunol. 2, 681-690 (2001). [Online Journal]