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 2134, perforin, and lipid rafts at the contact area of CTLs with EBV-positive targets. Blockade of 2134 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/2 beta 4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery.

Dupré, L., Andolfi, G., Tangye, S. G., Clementi, R., Locatelli, F., Aricò, M., Aiuti, A., Roncarolo, M., SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells, <<BLOOD>>, 2005; 105 (11): 4383-4389. [doi:10.1182/blood-2004-08-3269] [https://hdl.handle.net/10807/259982]

SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells

Locatelli, Franco;
2005

Abstract

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 2134, perforin, and lipid rafts at the contact area of CTLs with EBV-positive targets. Blockade of 2134 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/2 beta 4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery.
2005
Inglese
Dupré, L., Andolfi, G., Tangye, S. G., Clementi, R., Locatelli, F., Aricò, M., Aiuti, A., Roncarolo, M., SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells, <<BLOOD>>, 2005; 105 (11): 4383-4389. [doi:10.1182/blood-2004-08-3269] [https://hdl.handle.net/10807/259982]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/259982
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