title: Critical role for BIM in T cell receptor restimulation-induced death.
abstract: BACKGROUND
  Upon repeated or chronic antigen stimulation, activated T cells undergo a T cell receptor (TCR)-triggered propriocidal cell death important for governing the intensity of immune responses. This is thought to be chiefly mediated by an extrinsic signal through the Fas-FasL pathway. However, we observed that TCR restimulation still potently induced apoptosis when this interaction was blocked, or genetically impaired in T cells derived from autoimmune lymphoproliferative syndrome (ALPS) patients, prompting us to examine Fas-independent, intrinsic signals.
  
  
  RESULTS
  Upon TCR restimulation, we specifically noted a marked increase in the expression of BIM, a pro-apoptotic Bcl-2 family protein known to mediate lymphocyte apoptosis induced by cytokine withdrawal. In fact, T cells from an ALPS type IV patient in which BIM expression is suppressed were more resistant to restimulation-induced death. Strikingly, knockdown of BIM expression rescued normal T cells from TCR-induced death to as great an extent as Fas disruption.
  
  
  CONCLUSIONS
  Our data implicates BIM as a critical mediator of apoptosis induced by restimulation as well as growth cytokine withdrawal. These findings suggest an important role for BIM in eliminating activated T cells even when IL-2 is abundant, working in conjunction with Fas to eliminate chronically stimulated T cells and maintain immune homeostasis.
  
  
  METHODS
  This article was reviewed by Dr. Wendy Davidson (nominated by Dr. David Scott), Dr. Mark Williams (nominated by Dr. Neil Greenspan), and Dr. Laurence C. Eisenlohr.
authors: Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892-1508, USA. snowa@niaid.nih.gov
authors: Andrew L
authors: AL
authors: Snow
authors: João B
authors: JB
authors: Oliveira
authors: Lixin
authors: L
authors: Zheng
authors: Janet K
authors: JK
authors: Dale
authors: Thomas A
authors: TA
authors: Fleisher
authors: Michael J
authors: MJ
authors: Lenardo
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D000072224:Bcl-2-Like Protein 11; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D019014:fas Receptor / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; C491901:FAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor