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CD8+ T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides.

Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia. Department of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia. Laboratory-based Department, Royal College of Medicine Perak (UniLK-RCMP), Universiti Kuala Lumpur, Ipoh, Malaysia. Division of Infection Biology, Department of Life Sciences, School of Basic and Applied Sciences, Central University of Tamil Nadu (CUTN), Thiruvarur 610 005, India. Department of Social Work, Central University of Tamil Nadu (CUTN), Thiruvarur 610 005, India. Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, GA 30329, USA. Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden. Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia; Division of Infection Biology, Department of Life Sciences, School of Basic and Applied Sciences, Central University of Tamil Nadu (CUTN), Thiruvarur 610 005, India; Center of Excellence for Research in AIDS (CERiA), University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia. Electronic address: shankarem@cutn.ac.in.

Cellular immunology. 2017;:1-9
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Abstract

Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray™ following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide-stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-β1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-α, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence.