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Positive and negative signaling through SLAM receptors regulate synapse organization and thresholds of cytolysis
Fang Zhao1, Jennifer L Cannons, Mala Dutta
1Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
X-linked lymphoproliferative syndrome, characterized by fatal responses to Epstein-Barr virus infection, is caused by mutations affecting the adaptor SAP, which links SLAM family receptors to downstream signaling. Although cytotoxic defects in SAP-deficient T cells are documented, the mechanism remains unclear. We show that SAP-deficient murine CD8(+) T cells exhibited normal cytotoxicity against fibrosarcoma targets, yet had impaired adhesion to and killing of B cell and low-avidity T cell targets. SAP-deficient cytotoxic lymphocytes showed specific defects in immunological synapse organization with these targets, resulting in inefficient actin clearance. In the absence of SAP, signaling through the SLAM family members Ly108 and 2B4 resulted in increased recruitment of the SHP-1 phosphatase, associated with altered SHP-1 localization and decreased activation of Src kinases at the synapse. Hence, SAP and SLAM receptors regulate positive and negative signals required for organizing the T cell:B cell synapse and setting thresholds for cytotoxicity against distinct cellular targets.
Insights
X-linked lymphoproliferative syndrome arises from mutations in the adaptor SAP, impacting T cell responses to Epstein-Barr virus. SAP-deficient T cells show impaired synapse organization and cytotoxicity against specific targets.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- X-linked lymphoproliferative syndrome (XLP) is a severe genetic disorder characterized by fatal responses to Epstein-Barr virus (EBV) infection.
- Mutations in the adaptor protein SAP (SLAM-associated protein) are the primary cause of XLP, disrupting signaling pathways crucial for immune cell function.
- While cytotoxic defects in SAP-deficient T cells are known, the underlying mechanisms remain incompletely understood.
Purpose of the Study:
- To elucidate the precise mechanisms by which SAP deficiency impairs T cell cytotoxicity.
- To investigate the role of SLAM family receptors and associated signaling pathways in SAP-deficient cytotoxic lymphocytes.
- To understand how SAP influences the organization of the immunological synapse and target cell killing.
Main Methods:
- Utilized murine CD8(+) T cells deficient in SAP.
- Assessed cytotoxicity against various target cells (fibrosarcoma, B cells, low-avidity T cells).
- Analyzed immunological synapse formation, actin dynamics, and signaling pathways (SLAM, Ly108, 2B4, SHP-1, Src kinases).
Main Results:
- SAP-deficient CD8(+) T cells displayed normal cytotoxicity against fibrosarcoma targets but impaired adhesion and killing of B cells and low-avidity T cells.
- These cells exhibited defective immunological synapse organization with susceptible targets, including inefficient actin clearance.
- Absence of SAP led to increased SHP-1 phosphatase recruitment and altered localization, decreasing Src kinase activation at the synapse during SLAM family signaling.
Conclusions:
- SAP is critical for organizing the T cell:B cell immunological synapse and regulating cytotoxicity thresholds against different target cells.
- SAP-SLAM receptor interactions modulate both positive and negative signaling, essential for effective immune synapse formation and cytotoxic function.
- Understanding these pathways offers insights into XLP pathogenesis and potential therapeutic strategies for immune dysregulation.
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