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

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

Research output: Contribution to journalArticle

Abstract

The adaptor protein SAP regulates signaling through signaling lymphocytic activation molecule (SLAM)-famity 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.

Original languageEnglish
Pages (from-to)4383-4389
Number of pages7
JournalBlood
Volume105
Issue number11
DOIs
Publication statusPublished - Jun 1 2005

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T-cells
Human Herpesvirus 4
Viruses
T-Lymphocytes
Chemical activation
Polarization
T-Cell Antigen Receptor
Defects
Molecules
Hemophagocytic Lymphohistiocytosis
Perforin
Natural Killer T-Cells
Lymphoproliferative Disorders
Interleukin-4
Interferons
Machinery
Interleukin-2
Proteins
B-Lymphocytes
Down-Regulation

ASJC Scopus subject areas

  • Hematology

Cite this

Dupré, L., Andolfi, G., Tangye, S. G., Clementi, R., Locatelli, F., Aricò, M., ... Roncarolo, M. G. (2005). SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood, 105(11), 4383-4389. https://doi.org/10.1182/blood-2004-08-3269

SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. / Dupré, Loïc; Andolfi, Grazia; Tangye, Stuart G.; Clementi, Rita; Locatelli, Franco; Aricò, Maurizio; Aiuti, Alessandro; Roncarolo, Maria Grazia.

In: Blood, Vol. 105, No. 11, 01.06.2005, p. 4383-4389.

Research output: Contribution to journalArticle

Dupré, L, Andolfi, G, Tangye, SG, Clementi, R, Locatelli, F, Aricò, M, Aiuti, A & Roncarolo, MG 2005, 'SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells', Blood, vol. 105, no. 11, pp. 4383-4389. https://doi.org/10.1182/blood-2004-08-3269
Dupré L, Andolfi G, Tangye SG, Clementi R, Locatelli F, Aricò M et al. SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. Blood. 2005 Jun 1;105(11):4383-4389. https://doi.org/10.1182/blood-2004-08-3269
Dupré, Loïc ; Andolfi, Grazia ; Tangye, Stuart G. ; Clementi, Rita ; Locatelli, Franco ; Aricò, Maurizio ; Aiuti, Alessandro ; Roncarolo, Maria Grazia. / SAP controls the cytolytic activity of CD8+ T cells against EBV-infected cells. In: Blood. 2005 ; Vol. 105, No. 11. pp. 4383-4389.
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