The Role of SLAM-Associated Protein in T Cell Signaling and Apoptosis.

[摘要] X-linked Lymphoproliferative type 1 (XLP1) disease is a rare inherited syndrome characterized by generalized immunodeficiency, an extreme sensitivity to viral infections and a predisposition to the development of lymphoma. The disease is caused by loss-of-function mutations in the gene encoding the SLAM-associated protein (SAP). SAP is a SH2-domain-containing protein that interacts with the cytoplasmic tail of signaling receptors and protein tyrosine kinases to promote T cell activation following stimulation of the T cell receptor (TCR). T cell signaling regulates the balance between cell activation and death, and defects contribute to the lymphoproliferative nature of the disease. Previous studies have examined the various roles of SAP in modulating T cell responses, but these influences require further investigation, and are the focus of this study. To clarify the role of SAP in T cell signaling, we took a gene editing approach to disrupt the SAP gene and created a SAP-null T cell line. Through this approach we identified SAP-specific effects, which included cytokine production, transcription factor activity, and calcium mobilization. Interestingly, SAP-null cells exhibited a decrease in IL-2 expression, attributable to defective nuclear factor of activated T cells (NFAT) activation, and increased IFN-g production following TCR stimulation. Moreover, cells with SAP deficiencies have a heightened sensitivity to apoptotic stimuli. These results suggest that SAP defects drastically alter T cell activation and the cytokine environment, making T cells more sensitive to apoptotic stimuli, potentially impeding their ability to respond to immune challenges. Together, these results identify specific SAP-dependent defects in T cell signaling that could contribute to the characteristic phenotypes of patients with XLP1 disease.

[发布机构] University of Michigan

[效力级别] SLAM-Associated Protein (SAP)

[关键词] X-linked lymphoproliferative disease (XLP);SLAM-Associated Protein (SAP);Lymphoma;Epstein-Barr Virus (EBV);T Cell Signaling;T Cell Apoptosis;Microbiology and Immunology;Molecular;Cellular and Developmental Biology;Science;Cancer Biology