title: Activation induced cell death (AICD) of human melanoma antigen-specific TCR engineered CD8 T cells involves JNK, Bim and p53.
abstract: OBJECTIVE
  Adoptive cancer immunotherapy (ACT) with transgenic T cell receptor (TCR) engineered (TCReng) anti-tumor T cells has produced encouraging results, however, efficacy of these approaches need improvement. Since premature activation induced cell death (AICD) of adoptively administered T cells could be a major impediment, we examined the mechanism(s) underlying AICD in TCReng CD8+ cytolytic T lymphocytes (CTL).
  
  
  METHODS
  AICD in human tumor antigen-specific MHC class I restricted TCR engineered CD8+ CTL was induced by exposing them to cognate peptide epitope.
  
  
  RESULTS
  We show that TCReng CD8+ human primary CTL undergo AICD even upon encountering their cognate peptide epitope for the very first time. AICD in TCReng CTL is a death-receptor-independent, JNK activation-driven intrinsic processes, in which p53-mediated mitochondria-centric, non-transcription-dependent pathway plays an essential role. Activated JNK modulates mitochondrial membrane integrity in CTL undergoing AICD by directly interacting with Bcl family protein, Bim, and the mitochondrial membrane pore complex, voltage dependent anion channel (VDAC), leading to the release of caspase-independent death executioner, apoptosis inducing factor (AIF), accumulation of single strand DNA breaks and eventually to cell death.
  
  
  CONCLUSIONS
  Our findings offer opportunities to interfere with AICD in TCReng CD8+ anti-tumor CTL for sustaining them longer for producing better clinical outcomes.
authors.affiliation: a Department of Medicine , University of Connecticut Health Center , Farmington , CT , USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Chhabra
authors.affiliation: a Department of Medicine , University of Connecticut Health Center , Farmington , CT , USA.
authors.forename: Bijay
authors.initials: B
authors.lastname: Mukherji
authors.affiliation: a Department of Medicine , University of Connecticut Health Center , Farmington , CT , USA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Batra
mesh_terms: D051033:Apoptosis Inducing Factor / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016923:Cell Death / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053904:DNA Breaks, Single-Stranded; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D058950:Melanoma-Specific Antigens / Q000276:immunology; D051336:Mitochondrial Membranes / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D051033:Apoptosis Inducing Factor; D000072224:Bcl-2-Like Protein 11; D000939:Epitopes; D058950:Melanoma-Specific Antigens; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Activation Induced Cell Death (AICD); TCR engineering; cancer immunotherapy; melanoma; mitochondria-centric AICD