Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection
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Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection. / Nitschke, Katja; Flecken, Tobias; Schmidt, Julia; Gostick, Emma; Marget, Matthias; Neumann-Haefelin, Christoph; Blum, Hubert E; Price, David A; Thimme, Robert.
In: J VIROL, Vol. 89, No. 1, 01.2015, p. 25-34.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Tetramer enrichment reveals the presence of phenotypically diverse hepatitis C virus-specific CD8+ T cells in chronic infection
AU - Nitschke, Katja
AU - Flecken, Tobias
AU - Schmidt, Julia
AU - Gostick, Emma
AU - Marget, Matthias
AU - Neumann-Haefelin, Christoph
AU - Blum, Hubert E
AU - Price, David A
AU - Thimme, Robert
N1 - Copyright © 2015, Nitschke et al.
PY - 2015/1
Y1 - 2015/1
N2 - UNLABELLED: Virus-specific CD8(+) T cells are rarely detectable ex vivo by conventional methods during chronic hepatitis C virus (HCV) infection. In this study, however, we were able to detect and characterize HCV-specific CD8(+) T cells in all chronically HCV genotype 1a-infected, HLA-A*02:01-positive patients analyzed by performing major histocompatibility complex (MHC) class I tetramer enrichment. Two-thirds of these enriched HCV-specific CD8(+) T-cell populations displayed an effector memory phenotype, whereas, surprisingly, one-third displayed a naive-like phenotype despite ongoing viral replication. CD8(+) T cells with an effector memory phenotype could not expand in vitro, suggesting exhaustion of these cells. Interestingly, some of the naive-like CD8(+) T cells proliferated vigorously upon in vitro priming, whereas others did not. These differences were linked to the corresponding viral sequences in the respective patients. Indeed, naive-like CD8(+) T cells from patients with the consensus sequence in the corresponding T-cell epitope did not expand in vitro. In contrast, in patients displaying sequence variations, we were able to induce HCV-specific CD8(+) T-cell proliferation, which may indicate infection with a variant virus. Collectively, these data reveal the presence of phenotypically and functionally diverse HCV-specific CD8(+) T cells at very low frequencies that are detectable in all chronically infected patients despite viral persistence.IMPORTANCE: In this study, we analyzed CD8(+) T-cell responses specific for HLA-A*02:01-restricted epitopes in chronically HCV-infected patients, using MHC class I tetramer enrichment. Importantly, we could detect HCV-specific CD8(+) T-cell populations in all patients. To further characterize these HCV-specific CD8(+) T-cell populations that are not detectable using conventional techniques, we performed phenotypic, functional, and viral sequence analyses. These data revealed different mechanisms for CD8(+) T-cell failure in HCV infection, including T-cell exhaustion, viral escape, and functional impairment of naive-like HCV-specific CD8(+) T cells.
AB - UNLABELLED: Virus-specific CD8(+) T cells are rarely detectable ex vivo by conventional methods during chronic hepatitis C virus (HCV) infection. In this study, however, we were able to detect and characterize HCV-specific CD8(+) T cells in all chronically HCV genotype 1a-infected, HLA-A*02:01-positive patients analyzed by performing major histocompatibility complex (MHC) class I tetramer enrichment. Two-thirds of these enriched HCV-specific CD8(+) T-cell populations displayed an effector memory phenotype, whereas, surprisingly, one-third displayed a naive-like phenotype despite ongoing viral replication. CD8(+) T cells with an effector memory phenotype could not expand in vitro, suggesting exhaustion of these cells. Interestingly, some of the naive-like CD8(+) T cells proliferated vigorously upon in vitro priming, whereas others did not. These differences were linked to the corresponding viral sequences in the respective patients. Indeed, naive-like CD8(+) T cells from patients with the consensus sequence in the corresponding T-cell epitope did not expand in vitro. In contrast, in patients displaying sequence variations, we were able to induce HCV-specific CD8(+) T-cell proliferation, which may indicate infection with a variant virus. Collectively, these data reveal the presence of phenotypically and functionally diverse HCV-specific CD8(+) T cells at very low frequencies that are detectable in all chronically infected patients despite viral persistence.IMPORTANCE: In this study, we analyzed CD8(+) T-cell responses specific for HLA-A*02:01-restricted epitopes in chronically HCV-infected patients, using MHC class I tetramer enrichment. Importantly, we could detect HCV-specific CD8(+) T-cell populations in all patients. To further characterize these HCV-specific CD8(+) T-cell populations that are not detectable using conventional techniques, we performed phenotypic, functional, and viral sequence analyses. These data revealed different mechanisms for CD8(+) T-cell failure in HCV infection, including T-cell exhaustion, viral escape, and functional impairment of naive-like HCV-specific CD8(+) T cells.
KW - Adult
KW - Aged
KW - CD8-Positive T-Lymphocytes
KW - Cell Proliferation
KW - Female
KW - Hepacivirus
KW - Hepatitis C, Chronic
KW - Humans
KW - Immunologic Memory
KW - Male
KW - Middle Aged
KW - Phenotype
KW - T-Lymphocyte Subsets
KW - Young Adult
U2 - 10.1128/JVI.02242-14
DO - 10.1128/JVI.02242-14
M3 - SCORING: Journal article
C2 - 25320295
VL - 89
SP - 25
EP - 34
JO - J VIROL
JF - J VIROL
SN - 0022-538X
IS - 1
ER -