Selection of high-avidity CD8 T cells correlates with control of hepatitis C virus infection.
Both strong antigenic avidity and acquisition of proper effector functions contribute to the efficacy of antiviral T cell responses. To correlate these parameters with the outcome of hepatitis C virus (HCV) infection, we characterized HCV-specific CD8 T cell lines isolated after immunomagnetic sorting of peripheral blood mononuclear cells from human leukocyte antigen A*02 (HLA-A*02) individuals with various HCV serological statuses, using recombinant HLA-A*0201 multimers loaded with three immunodominant HCV genotype 1-derived epitopes. CD8 T cells specific for these three epitopes were derived from most HLA-A*0201 individuals, regardless of their HCV serology or clinical outcome. Donors recovered from genotype 1 HCV infection were enriched for high-avidity T cells with enhanced interferon gamma (IFN-gamma), tumor necrosis factor alpha, and cytotoxic T lymphocyte responses, when compared with seronegative donors and seropositive patients infected with irrelevant HCV genotypes. Patients chronically infected with genotype 1 strain yielded almost exclusively low-avidity T cells, whose hyporesponsiveness was primarily attributable to low T cell receptor (TCR) avidity rather than intrinsic functional defects.


CONCLUSIONS
This study suggests that strong IFN-gamma responses associated with efficient viral clearance primarily result from Ag-driven selection/survival of HCV-specific T cells expressing high-avidity TCR. It also suggests a link between the quality of the initial HCV-specific T cell repertoire and susceptibility to chronic infection.
Neveu
Bérangère
B
Institut National de la Santé et de la Recherche Médicale, U892, Centre de Recherches en Cancérologie, Nantes, France.
Debeaupuis
Emilie
E
Echasserieau
Klara
K
le Moullac-Vaidye
Béatrice
B
Gassin
Michelle
M
Jegou
Loïg
L
Decalf
Jérémie
J
Albert
Matthew
M
Ferry
Nicolas
N
Gournay
Jérôme
J
Houssaint
Elisabeth
E
Bonneville
Marc
M
Saulquin
Xavier
X
D000915:Antibody Affinity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen; D016174:Hepacivirus / Q000276:immunology; D006526:Hepatitis C / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C524866:HLA-A*02 antigen; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma