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Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency
Andrew L. Snow, … , Jack J. Bleesing, Michael J. Lenardo
Andrew L. Snow, … , Jack J. Bleesing, Michael J. Lenardo
Published September 14, 2009
Citation Information: J Clin Invest. 2009;119(10):2976-2989. https://doi.org/10.1172/JCI39518.
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Research Article Immunology Article has an altmetric score of 3

Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency

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Abstract

X-linked lymphoproliferative disease (XLP) is a rare congenital immunodeficiency that leads to an extreme, usually fatal increase in the number of lymphocytes upon infection with EBV. It is most commonly defined molecularly by loss of expression of SLAM-associated protein (SAP). Despite this, there is little understanding of how SAP deficiency causes lymphocytosis following EBV infection. Here we show that T cells from individuals with XLP are specifically resistant to apoptosis mediated by TCR restimulation, a process that normally constrains T cell expansion during immune responses. Expression of SAP and the SLAM family receptor NK, T, and B cell antigen (NTB-A) were required for TCR-induced upregulation of key pro-apoptotic molecules and subsequent apoptosis. Further, SAP/NTB-A signaling augmented the strength of the proximal TCR signal to achieve the threshold required for restimulation-induced cell death (RICD). Strikingly, TCR ligation in activated T cells triggered increased recruitment of SAP to NTB-A, dissociation of the phosphatase SHP-1, and colocalization of NTB-A with CD3 aggregates. In contrast, NTB-A and SHP-1 contributed to RICD resistance in XLP T cells. Our results reveal what we believe to be novel roles for NTB-A and SAP in regulating T cell homeostasis through apoptosis and provide mechanistic insight into the pathogenesis of lymphoproliferative disease in XLP.

Authors

Andrew L. Snow, Rebecca A. Marsh, Scott M. Krummey, Philip Roehrs, Lisa R. Young, Kejian Zhang, Jack van Hoff, Deepali Dhar, Kim E. Nichols, Alexandra H. Filipovich, Helen C. Su, Jack J. Bleesing, Michael J. Lenardo

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Figure 3

Ectopic expression of SAP restores RICD in XLP Pt4 T cells.

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Ectopic expression of SAP restores RICD in XLP Pt4 T cells.
(A) Jurkat c...
(A) Jurkat cells were transfected with pVenus-SAP or pVenus alone and lysed after 48 hours. Lysates were separated by SDS-PAGE and immunoblotted with anti-SAP Ab. β-Actin served as a loading control. (B) Activated XLP Pt4 PBLs were transfected with pVenus-SAP or pVenus alone and incubated overnight. After removal of dead cells, cells were restimulated with 500 ng/ml OKT3 for 8–24 hours. Apoptosis was measured by Annexin V staining. The additional Annexin V+ gate in the top right quadrants excluded Venus+ cells that could not be compensated due to bright fluorescence. (C) Transfected cells were treated as described in B. The percentage of cell loss was calculated based on viable cells present before and after restimulation.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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