title: Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation.
abstract: Exhausted CD8+ T cell responses during chronic viral infections are defined by a complex expression pattern of inhibitory receptors. However, very little information is currently available about the coexpression patterns of these receptors on human virus-specific CD8+ T cells and their correlation with antiviral functions, T cell differentiation and antigen recognition. We addressed these important aspects in a cohort of 38 chronically HCV infected patients and found a coexpression of inhibitory receptors such as 2B4, CD160 and KLRG1 in association with PD-1 in about half of the HCV-specific CD8+ T cell responses. Importantly, this exhaustive phenotype was associated with low and intermediate levels of CD127 expression, an impaired proliferative capacity, an intermediate T cell differentiation stage and absence of sequence variations within the corresponding epitopes, indicating ongoing antigen triggering. In contrast, a low expression of inhibitory receptors by the remaining HCV-specific CD8+ T cells occurred in concert with a CD127hi phenotype, an early T cell differentiation stage and presence of viral sequence variations within the corresponding epitopes. In sum, these results suggest that T cell exhaustion contributes to the failure of about half of HCV-specific CD8+ T cell responses and that it is determined by a complex interplay of immunological (e.g. T cell differentiation) and virological (e.g. ongoing antigen triggering) factors.
authors.affiliation: Department of Medicine II, University of Freiburg, Freiburg, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Bengsch
authors.forename: Bianca
authors.initials: B
authors.lastname: Seigel
authors.forename: Marianne
authors.initials: M
authors.lastname: Ruhl
authors.forename: Jörg
authors.initials: J
authors.lastname: Timm
authors.forename: Martin
authors.initials: M
authors.lastname: Kuntz
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Hanspeter
authors.initials: H
authors.lastname: Pircher
authors.forename: Robert
authors.initials: R
authors.lastname: Thimme
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D016174:Hepacivirus / Q000302:isolation & purification; D006526:Hepatitis C / Q000276:immunology* / Q000821:virology; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D008213:Lymphocyte Activation; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000378:metabolism*; D000071176:Signaling Lymphocytic Activation Molecule Family; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism*; D019562:Viral Load
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C114505:CD160 protein, human; C084093:CD244 protein, human; D058851:GPI-Linked Proteins; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D015534:Trans-Activators