title: Inhibition of c-Jun N-terminal kinase rescues influenza epitope-specific human cytolytic T lymphocytes from activation-induced cell death.
abstract: Cytolytic T lymphocytes (CTL) play an important role in defense against viral infections. Following clonal expansion and effector functions, a vast majority of the antigen-specific CTL undergoes programmed cell death to maintain homeostasis. We have shown earlier that melanoma epitope-specific CTL are quite sensitive to activation-induced cell death (AICD) even on the secondary encounter of the antigen. Excessive sensitivity of viral antigen-specific CTL to AICD, however, would be counterproductive. It might be argued that although CTL for a "self" epitope might be more prone to AICD for maintaining self-tolerance, viral antigen-specific CTL are likely to be less sensitive to AICD. We show here that influenza matrix protein-derived MP(58-66) epitope-specific CTL, activated in vitro and bearing a memory phenotype, are just as sensitive to AICD. The AICD in these CTL is not blocked by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone or by soluble Ig-Fc chimeras of the death receptors [Fas, TNF receptor (TNF-R), TRAIL-RI, TRAIL-RII]. However, the MP(58-66)-specific CTL can be rescued from AICD by the c-jun-N-terminal kinase (JNK) inhibitor SP600125. These results have implications for immunotherapeutic intervention in rescuing viral epitope-specific CTL from AICD.
authors.affiliation: Department of Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Shikhar
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Arvind
authors.initials: A
authors.lastname: Chhabra
authors.forename: Upendra
authors.initials: U
authors.lastname: Hegde
authors.forename: Nitya G
authors.initials: NG
authors.lastname: Chakraborty
authors.forename: Bijay
authors.initials: B
authors.lastname: Mukherji
mesh_terms: D000873:Anthracenes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000032:analysis; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D009980:Influenza A virus / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: D000873:Anthracenes; D015415:Biomarkers; D018984:Epitopes, T-Lymphocyte; D047428:Protein Kinase Inhibitors; D014763:Viral Matrix Proteins; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases