Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection
Daniele Accapezzato, … , Mario U. Mondelli, Vincenzo Barnaba
Daniele Accapezzato, … , Mario U. Mondelli, Vincenzo Barnaba
Published April 1, 2004
Citation Information: J Clin Invest. 2004;113(7):963-972. https://doi.org/10.1172/JCI20515.
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Categories: Article Immunology

Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection

Abstract

Regulatory T (TR) cells consist of phenotypically and functionally distinct CD4+ and CD8+ T cell subsets engaged both in maintaining self-tolerance and in preventing anti–non-self effector responses (microbial, tumor, transplant, and so on) that may be harmful to the host. Here we propose that the proinflammatory function of virus-specific memory effector CCR7–CD8+ T cells, which are massively recruited in the liver, are inefficient (in terms of IFN-γ production) in patients with chronic hepatitis C virus (HCV) infection because of the concomitant presence of virus-specific CCR7–CD8+ TR cells producing considerable amounts of IL-10. These CD8+ TR cells are antigen specific, as they can be stimulated by HCV epitopes and suppress T cell responses that are in turn restored by the addition of neutralizing anti–IL-10. This study provides for the first time to our knowledge direct evidence of the existence of virus-specific CD8+ TR cells that infiltrate the livers of patients with chronic HCV infection, identifies IL-10 as a soluble inhibitory factor mediating suppression, and suggests that these cells play a pivotal role in controlling hepatic effector CD8+ T cell responses.

Authors

Daniele Accapezzato, Vittorio Francavilla, Marino Paroli, Marco Casciaro, Lucia Valeria Chircu, Agostino Cividini, Sergio Abrignani, Mario U. Mondelli, Vincenzo Barnaba

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Figure 6

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IL-2 drives virus-specific CCR7– cells to terminate the effector cell pr...
IL-2 drives virus-specific CCR7– cells to terminate the effector cell program. (A and B) Two independent experiments, in which LIL pools derived from two biopsies (for each experiment) of HLA-A2+ patients, were cultured with 50 U/ml IL-2 for 3 days. Then, cells were stained with TC-labeled mAb to CD8, and the pool of PE-labeled HLA-A2.1+ mix tetramer stimulated with the corresponding peptides and autologous PBMCs as APCs for 6 hours, and stained intracellularly with FITC-labeled mAb to IFN-γ. Dot plots are gated on tetramer+CD8+ cells. Results are expressed as percentage of cells. Null, no stimulus. (C) Fresh peripheral (p)CCR7+ and CCR7– cells purified from PBMCs of the patients presented in A were cultured with IL-2 as described above and stained with FITC-labeled mAb to CD8 and PE-Cy5–labeled HLA-A2.1+ tetramers expressing NS41851–1859. Then, cells were stimulated with autologous APCs and NS41851–1859 peptide for 6 hours and were stained intracellularly with PE-labeled mAb to IFN-γ. Dot plots are gated on tetramer+CD8+ cells. Results are expressed as percentage of cells.