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
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