Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency
Autor: | Andrew L. Snow, Kejian Zhang, Rebecca A. Marsh, Kim E. Nichols, Lisa R. Young, Jack van Hoff, Helen C. Su, Alexandra H. Filipovich, Michael J. Lenardo, Jack J. Bleesing, Philip A. Roehrs, Deepali Dhar, Scott M. Krummey |
---|---|
Rok vydání: | 2009 |
Předmět: |
Programmed cell death
Fas Ligand Protein T-Lymphocytes CD3 T cell Receptors Antigen T-Cell Lymphoproliferative disorders Apoptosis Receptors Cell Surface Biology Mice Immune system Signaling Lymphocytic Activation Molecule Family Member 1 Antigen Antigens CD Signaling Lymphocytic Activation Molecule Family Proto-Oncogene Proteins medicine Animals Humans Signaling Lymphocytic Activation Molecule Associated Protein Bcl-2-Like Protein 11 Gene Expression Profiling T-cell receptor Intracellular Signaling Peptides and Proteins Membrane Proteins X-linked lymphoproliferative disease General Medicine Microarray Analysis medicine.disease Lymphoproliferative Disorders medicine.anatomical_structure Immunology biology.protein RNA Interference Apoptosis Regulatory Proteins Signal Transduction Research Article |
Zdroj: | Journal of Clinical Investigation. |
ISSN: | 0021-9738 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |