SAP Controls the Cytolytic Activity of CD8+ T Cells Against EBV-infected Cells
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The adaptor protein SAP regulates signaling through signaling lymphocytic activation molecule (SLAM)-family receptors expressed on T and natural killer (NK) cells. In patients affected by X-linked lymphoproliferative (XLP) disease, mutations in the SH2D1A gene result in defective lytic activity. However, the mechanism by which SAP controls cytotoxic activity remains unclear. T-cell-receptor (TCR) activation of CD8(+) cytotoxic T cells (CTLs) results in down-regulation of SAP, suggesting that this protein is involved in early activation events. Here, we show that SAP-deficient CTLs from patients with XLP and hemophagocytic lymphohistiocytosis (HLH) display a specific lytic defect against autologous and allogeneic Epstein-Barr virus (EBV)-positive B cells. This defect is associated with the defective polarization of 2B4, perforin, and lipid rafts at the contact area of CTLs with EBV-positive targets. Blockade of 2B4 in normal CTLs reproduces the defects in lysis and polarization observed in SAP-deficient CTLs. Expression and regulation of the SLAM-family receptors SLAM, CD84, and 2B4, as well as the lytic effectors perforin and granzyme-B are normal in SAP-deficient CTLs. In addition, TCR stimulation leads to normal proliferation and production of interleukin 2 (IL-2), IL-4, and interferon-gamma (IFN-gamma). These results demonstrate that the SAP/2B4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery.
Monel B, Lamothe P, Meyo J, McLean A, Quinones-Alvarado R, Laporte M bioRxiv. 2025; .
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Matsushima R, Wakamatsu E, Machiyama H, Nishi W, Yoshida Y, Nishikawa T iScience. 2025; 28(1):111669.
PMID: 39886466 PMC: 11780131. DOI: 10.1016/j.isci.2024.111669.
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Xiao L, Zhang L, Guo C, Xin Q, Gu X, Jiang C Cancer Commun (Lond). 2024; 44(7):791-832.
PMID: 38923737 PMC: 11260773. DOI: 10.1002/cac2.12579.