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

J Clin Invest. 2009 Oct;119(10):2976-89. doi: 10.1172/JCI39518. Epub 2009 Sep 14.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • Apoptosis / physiology*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology
  • Bcl-2-Like Protein 11
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / metabolism
  • Gene Expression Profiling
  • Humans
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Lymphoproliferative Disorders / immunology*
  • Lymphoproliferative Disorders / physiopathology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology
  • Mice
  • Microarray Analysis
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / immunology
  • RNA Interference
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / immunology
  • Signal Transduction / physiology
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Signaling Lymphocytic Activation Molecule Family Member 1
  • T-Lymphocytes / cytology
  • T-Lymphocytes / physiology*


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Bcl2l11 protein, mouse
  • FASLG protein, human
  • Fas Ligand Protein
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Receptors, Antigen, T-Cell
  • Receptors, Cell Surface
  • SH2D1A protein, human
  • SLAMF6 protein, human
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Slamf6 protein, mouse
  • Signaling Lymphocytic Activation Molecule Family Member 1