Details

Autor(en) / Beteiligte

• Dupré, Loïc
• Andolfi, Grazia
• Tangye, Stuart G.
• Clementi, Rita
• Locatelli, Franco
• Aricò, Maurizio
• Aiuti, Alessandro
• Roncarolo, Maria-Grazia

Titel

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

Ist Teil von

• Blood, 2005-06, Vol.105 (11), p.4383-4389

Ort / Verlag

Washington, DC: Elsevier Inc

Erscheinungsjahr

2005

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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-γ (IFN-γ). 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.