Solomon Owusu Sekyere1, Pothakamuri Venkata Suneetha1, Anke Renate Maria Kraft1, Shihong Zhang1, Julia Dietz2, Christoph Sarrazin2, Michael Peter Manns1, Verena Schlaphoff3, Markus Cornberg4, Heiner Wedemeyer5. 1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 2. Department of Internal Medicine 1, J. W. Goethe University Hospital, Frankfurt am Main, Germany. 3. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: Schlaphoff.Verena@mh-hannover.de. 4. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: Cornberg.Markus@mh-hannover.de. 5. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. Electronic address: Wedemeyer.Heiner@mh-hannover.de.
Abstract
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.
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.
Authors: Nina C Sabins; Benjamin C Harman; Linda R Barone; Shixue Shen; Sandra Santulli-Marotto Journal: Front Immunol Date: 2016-06-16 Impact factor: 7.561