期刊
GASTROENTEROLOGY
卷 134, 期 7, 页码 1927-1937出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2008.02.033
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资金
- Medical Research Council [G0501963] Funding Source: researchfish
- Medical Research Council [G0501963] Funding Source: Medline
- NCI NIH HHS [P30 CA016520] Funding Source: Medline
- NCRR NIH HHS [M01-RR00040, M01 RR000040] Funding Source: Medline
- NIAAA NIH HHS [R01 AA012849, R01 AA012849-05, AA12849] Funding Source: Medline
- NIAID NIH HHS [R01 AI047519-09, AI47519, P01 AI056299, R01 AI047519-08, R01 AI047519, AI56299] Funding Source: Medline
- NIDDK NIH HHS [P30DK50306, P30 DK050306] Funding Source: Medline
- MRC [G0501963] Funding Source: UKRI
Background & Aims: The immunoinhibitory receptor programmed death-1 (PD-1) is up-regulated on dysfunctional virus-specific CD8 T cells during chronic viral infections, and blockade of PD-1/PD-ligand (PD-L) interactions can restore their function. As hepatitis C virus (HCV) persists in the liver with immune-mediated disease pathogenesis, we examined the role of PD-1/PD-L pathway in antigen-specific CD8 T-cell dysfunction in the liver and blood of HCV-infected patients. Methods: PD-1 expression and function of circulating CD8 T cells specific for HCV, Epstein-Barr virus, and influenza virus were examined ex vivo and following antigenic stimulation in vitro in patients with acute, chronic, and resolved HCV infection using class I tetramers and flow cytometry. Intrahepatic CD8 T cells were examined from liver explants of chronically HCV-infected transplant recipients. Results: Intrahepatic HCV-specific CD8 T cells from chronically HCV-infected patients were highly PD-1 positive, profoundly dysfunctional, and unexpectedly refractory to PD-1/PD-L blockade, contrasting from circulating PD-1-intermediate HCV-specific CD8 T cells with responsiveness to PD-1/PD-L blockade. This intrahepatic functional impairment was HCV-specific and directly associated with the level of PD-1 expression. Highly PD-1-positive intrahepatic CD8 T cells were more phenotypically exhausted with increased cytotoxic T-lymphocyte antigen 4 and reduced CD28 and CD127 expression, suggesting that active antigen-specific stimulation in the liver induces a profound functional exhaustion not reversible by PD-1/PD-L blockade alone. Conclusions: HCV-specific CD8 T-cell dysfunction and responsiveness to PD-1/PD-L blockade are defined by their PD-1 expression and compartmentalization. These findings provide new and clinically relevant insight to differential antigen-specific CD8 T-cell exhaustion and their functional restoration.
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