title: CD8+ T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides.
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.
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Muttiah
authors.initials: M
authors.lastname: Barathan
authors.affiliation: Department of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Rosmawati
authors.initials: R
authors.lastname: Mohamed
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Jamuna
authors.initials: J
authors.lastname: Vadivelu
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Li Yen
authors.initials: LY
authors.lastname: Chang
authors.affiliation: Laboratory-based Department, Royal College of Medicine Perak (UniLK-RCMP), Universiti Kuala Lumpur, Ipoh, Malaysia.
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Vignesh
authors.affiliation: Division of Infection Biology, Department of Life Sciences, School of Basic and Applied Sciences, Central University of Tamil Nadu (CUTN), Thiruvarur 610 005, India.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Krishnan
authors.affiliation: Department of Social Work, Central University of Tamil Nadu (CUTN), Thiruvarur 610 005, India.
authors.forename: Panneer
authors.initials: P
authors.lastname: Sigamani
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: Alireza
authors.initials: A
authors.lastname: Saeidi
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603 Kuala Lumpur, Malaysia.
authors.forename: M Ravishankar
authors.initials: MR
authors.lastname: Ram
authors.affiliation: Department of Microbiology and Immunology, Emory Vaccine Center, Atlanta, GA 30329, USA.
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Velu
authors.affiliation: Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, 58185 Linköping, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Larsson
authors.affiliation: 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.
authors.forename: Esaki M
authors.initials: EM
authors.lastname: Shankar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002478:Cells, Cultured; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D000068884:Immunosenescence; D018836:Inflammation Mediators / Q000378:metabolism; D008875:Middle Aged; D010446:Peptide Fragments / Q000276:immunology; D019562:Viral Load; D055815:Young Adult
chemical_list: D000956:Antigens, Viral; D061025:Costimulatory and Inhibitory T-Cell Receptors; D016207:Cytokines; D018836:Inflammation Mediators; D010446:Peptide Fragments
keywords: Co-inhibitory receptors; HCV; Immune checkpoint; PD-1; T-cell exhaustion; TIM-3