Activation-induced cell death of human melanoma specific cytotoxic T lymphocytes is mediated by apoptosis-inducing factor.
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.
Chhabra
Arvind
A
Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, USA.
Mehrotra
Shikhar
S
Chakraborty
Nitya G
NG
Dorsky
David I
DI
Mukherji
Bijay
B
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
D000873:Anthracenes; D051033:Apoptosis Inducing Factor; C432165:pyrazolanthrone