RESUMO
BACKGROUND & AIMS: The functionality of virus-specific T cells is regulated by a sophisticated network of an expanding repertoire of co-regulatory receptors, which could be harnessed for immunotherapeutic applications. However, targeting particular pathways during persistent virus infections has resulted in variable outcomes. The extent to which T cell exhaustion can be reversed, by targeting multiple co-regulatory pathways, still remains not fully investigated. METHODS: We analysed the phenotype and in vitro functionality of HCV-specific CD8(+) T cells expressing PD-1, CTLA-4, TIM-3 or 2B4 either alone or in various combinations and compared expression levels to those of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) specific T cells in peripheral blood mononuclear cells (PBMCs) from the same cohort of patients with chronic hepatitis C (CHC) infection. RESULTS: Blockade and/or crosslinking of distinct co-regulatory pathways in exhausted HCV-specific CD8(+) T cells resulted in rather diverse and individualized T cell responses, irrespective of the type and number of receptors targeted. Overall, in vitro manipulations of these pathways yielded three response possibilities: (i) total non-response (ii) good single blockade response and (iii) good dual/multiple blockade response, with each comprising approximately one-third of the patients tested. The diversity of the in vitro responsiveness of HCV-specific T cells was reflected by an enormous ex vivo phenotypic heterogeneity. Despite this broad heterogeneity, HCV-specific CD8(+) T cells differed from EBV- and CMV-specific T cells in particular by TIM-3 expression, which also correlated with liver disease activity and viral load. CONCLUSIONS: HCV-specific CD8(+) T cell functionality, upon co-regulatory receptor manipulations, was characterized by an individual pattern of responses in patients with CHC, suggesting that treatment approaches, targeting these receptors, should consider inter-individual differences and be personalized.