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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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 8

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HCV antigens induce regulatory CD8+ T cells. (A–D) Four independent expe...
HCV antigens induce regulatory CD8+ T cells. (A–D) Four independent experiments showing that LILs derived from four HLA-A2+ patients suppress HCV-specific proliferation by autologous PBMCs only when stimulated with HCV peptides (HCVLILs) but not when left unstimulated (LILs). In particular, HLA-A2+ PBMCs were cocultured with autologous LILs in the presence or absence of both HLA-A2–related HCV peptides (NS31073–1081, NS31406–1415, and NS41851–1859) and soluble recombinant chimeric NS3/NS4. In some wells, anti–IL-10 Ab was added. (E and F) Two control experiments showing that LILs derived from two HLA-A2+ patients suppress HCV-specific proliferation by autologous PBMCs only when stimulated with HCV peptides (HCVLILs) but not when stimulated with irrelevant HLA-A2–related HIV peptides (pol919–927, nef94–102, and env49–57) (HIVLILs). After 6 days of coculture, 1 μCi [3H]thymidine was added to the cultures and the radioactivity incorporated by cells was determined after 18 hours. The cpm values of PBMCs (in the absence of LILs) in response to NS3/NS4 were calculated after subtraction of background and are indicated in parenthesis. The percent of suppression was calculated with the following formula: (PBMC-LIL coculture cpm / PBMC cpm) × 100.