title: Activation-induced cell death of human melanoma specific cytotoxic T lymphocytes is mediated by apoptosis-inducing factor.
abstract: Activation-induced cell death (AICD) of T cells can be an impediment towards achieving a robust and long-lived cytolytic T lymphocyte (CTL) response from active specific immunization or after adoptive cell transfer in cancer immunotherapy. The mechanism of AICD in primary CTL, however, remains poorly understood. It is widely believed that AICD is driven by signals from death receptors (DR) and that the cell death takes place in a caspase-dependent manner, although it has been shown that AICD of T cells can be induced by internal triggers and that death takes place in a caspase-independent manner. We show here that AICD in human melanoma epitope-specific primary CTL involves selective mitochondrio-nuclear translocation of the apoptosis inducing factor (AIF) without cytochrome c release, caspase-3 and caspase-8 activation, and results from large-scale DNA fragmentation. The c-jun-N terminal kinase (JNK) inhibitor, SP600125, blocks the mitochondrio-nuclear translocation of AIF and prevents AICD in these CTL. These findings suggest that the AICD in human melanoma epitope specific primary CTL is mediated by mitochondrial AIF release and JNK is involved in regulation of this death process.
authors.affiliation: Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Chhabra
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Nitya G
authors.initials: NG
authors.lastname: Chakraborty
authors.forename: David I
authors.initials: DI
authors.lastname: Dorsky
authors.forename: Bijay
authors.initials: B
authors.lastname: Mukherji
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051033:Apoptosis Inducing Factor / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000873:Anthracenes; D051033:Apoptosis Inducing Factor; C432165:pyrazolanthrone