Controversy on the role of FoxP3+ regulatory T cells in fibrogenesis in chronic hepatitis C virus infections

Intrahepatic IL-8 producing Foxp3+CD4+ regulatory T cells and fibrogenesis in chronic hepatitis CJournal of HepatologyVol. 59Issue 2PreviewRegulatory CD4+ T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions. Full-Text PDF Reply to: “Controversy on the role of FoxP3+ regulatory T cells in fibrogenesis in chronic hepatitis C virus infections”Journal of HepatologyVol. 60Issue 1PreviewTo the Editor: Full-Text PDF Open Access To the Editor: We read with interest the manuscript by Langhans and colleagues. The authors identified a subset of intrahepatic FoxP3+ regulatory T cells (Treg) that produce IL-8 in chronic hepatitis C virus (HCV) infected patients, and the authors suggested that these cells promote liver fibrosis through stimulation of hepatic stellate cells [[1]Langhans B. Kramer B. Louis M. Nischalke H.D. Huneburg R. Staratschek-Jox A. et al.Intrahepatic IL-8 producing Foxp3(+)CD4(+) regulatory T cells and fibrogenesis in chronic hepatitis C.J Hepatol. 2013; 59: 229-235Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. This article is very timely and highly relevant in an age where novel therapeutic strategies based on the use of direct-acting antivirals are expected to lead to viral eradication in most chronic HCV patients who undergo treatment. However, despite dramatically improved viral eradication rates, the detrimental consequences of liver pathology and fibrosis, such as decompensated liver cirrhosis and hepatocellular carcinoma, remain an issue, and detailed understanding of fibrosis is needed. The paper by Langhans et al. makes an important contribution to better understand the role of Treg in fibrosis in chronic HCV by showing that IL-8-secreting Treg are enriched in the liver and are detected especially at the transition areas of fibrosis. Although this is a very intriguing observation that identifies a functionally specialized fraction within the Treg pool of cells, it also raises a number of questions. First of all, only a minority of liver FoxP3+ Treg produce IL-8 (on average 4.5%), while it is known that Kupffer cells, but also hepatocytes, endothelial cells, epithelial cells and fibroblasts are major sources of IL-8. The paper does not clarify what determines that Treg-derived IL-8 promotes fibrinogenesis, whereas the importance of IL-8 derived from other liver cells is still unknown. Importantly, the IL-8 levels secreted by these cells are likely magnitudes higher. Next, an interesting finding from the microarray analysis presented by the authors is that Treg clones generated from cells from chronic HCV patients also express IFN-γ, besides IL-8. Both cytokines are expressed at lower levels by clones from patients with spontaneously resolved HCV infections. It would be relevant to examine whether the IL-8/IFN-γ producing Treg clones also possess effector activities that are independent of IL-8 and may promote fibrosis. In this respect it is important to mention that a general feature of tissue-residing T cells is an activated phenotype [[2]Sathaliyawala T. Kubota M. Yudanin N. Turner D. Camp P. Thome J.J.C. et al.Distribution and compartmentalization of human circulating and tissue-resident memory T cell subsets.Immunity. 2013; 38: 178-197Abstract Full Text Full Text PDF Scopus (587) Google Scholar], which may be more pronounced in livers from persistent vs. resolved patients. Finally, IFN-γ producing capacity is generally not a feature of FoxP3+ Treg, which raises the question whether the Treg clones described by Langhans et al., are representative for intrahepatic FoxP3+ Treg in vivo. In apparent contradiction with the population of IL-8 secreting Treg described by Langhans et al., we recently published data in the Journal of Hepatology in line with the widely accepted paradigm that FoxP3+ Treg limit immunopathology at the cost of insufficient protective pathogen-specific immune responses [3Belkaid Y. T Regulatory Cells and infection: a dangerous necessity.Nat Rev Immunol. 2007; 7: 875-888Crossref PubMed Scopus (589) Google Scholar, 4Claassen M.A. de Knegt R.J. Tilanus H.W. Janssen H.L. Boonstra A. Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis.J Hepatol. 2010; 52: 315-321Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. Our findings showed that FoxP3+ Treg were abundantly present in chronic HCV infected livers, but not in healthy livers, and primarily resided within the portal tracts in close proximity to the lymphocytic infiltrate, which is in line with previous findings published in the Journal of Hepatology by two independent groups [5Sturm N. Thelu M.A. Camous X. Dimitrov G. Ramzan M. Dufeu-Duchesne T. et al.Characterization and role of intra-hepatic regulatory T cells in chronic hepatitis C pathogenesis.J Hepatol. 2010; 53: 25-35Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 6Ward S.M. Fox B.C. Brown P.J. Worthington J. Fox S.B. Chapman R.W. et al.Quantification and localisation of FOXP3+ T lymphocytes and relation to hepatic inflammation during chronic HCV infection.J Hepatol. 2007; 47: 316-324Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar]. Additionally, in our hands, higher frequencies of FoxP3+ Treg were present in livers of chronic HCV patients without or with mild fibrosis [[4]Claassen M.A. de Knegt R.J. Tilanus H.W. Janssen H.L. Boonstra A. Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis.J Hepatol. 2010; 52: 315-321Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar]. Although Langhans and colleagues kindly referred to our publication, they omitted to discuss these key findings. If it holds true that IL-8 production by FoxP3+ Treg substantially contributes to liver fibrosis, we propose that, analogous to TGF-β [7Friedman S.L. Mechanisms of hepatic fibrogenesis.Gastroenterology. 2008; 134: 1655-1669Abstract Full Text Full Text PDF PubMed Scopus (2209) Google Scholar, 8Li S. Vriend L.E. Nasser I.A. Popov Y. Afdhal N.H. Koziel M.J. et al.Hepatitis C virus-specific T-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis.Hepatology. 2012; 56: 2094-2105Crossref PubMed Scopus (23) Google Scholar, 9Rallon N.I. Barreiro P. Soriano V. Garcia-Samaniego J. Lopez M. Benito J.M. Elevated TGF-beta1 levels might protect HCV/ HIV-coinfected patients from liver fibrosis.Eur J Clin Invest. 2011; 41: 70-76Crossref PubMed Scopus (21) Google Scholar], FoxP3+ Treg play a dual role both promoting and limiting fibrosis. While FoxP3+ Treg generally seem to protect against liver fibrosis [[4]Claassen M.A. de Knegt R.J. Tilanus H.W. Janssen H.L. Boonstra A. Abundant numbers of regulatory T cells localize to the liver of chronic hepatitis C infected patients and limit the extent of fibrosis.J Hepatol. 2010; 52: 315-321Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar], the small subset of IL-8-expressing FoxP3+ Treg may deteriorate liver pathology [[1]Langhans B. Kramer B. Louis M. Nischalke H.D. Huneburg R. Staratschek-Jox A. et al.Intrahepatic IL-8 producing Foxp3(+)CD4(+) regulatory T cells and fibrogenesis in chronic hepatitis C.J Hepatol. 2013; 59: 229-235Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. Importantly, in contrast to what is often postulated, we recently showed that FoxP3+ Treg are retained in the liver long after HCV eradication, even after HCV RNA was undetectable in serum for more than 12 months, suggesting ongoing immunopathology and regulation by intrahepatic FoxP3+ Treg [[10]Claassen M.A. de Knegt R.J. Janssen H.L. Boonstra A. Retention of CD4+CD25+FoxP3+ regulatory T cells in the liver after therapy-induced hepatitis C virus eradication in humans.J Virol. 2011; 85: 5323-5330Crossref PubMed Scopus (31) Google Scholar]. These FoxP3+ Treg differed phenotypically from their counterparts present during ongoing persistent infection. We strongly feel that these Treg are unlikely to further promote fibrosis in the absence of HCV, but rather act as memory Treg. The question remains whether IL-8 production by FoxP3+ Treg is maintained after viral eradication, or whether IL-8 expression is reduced. Our data as well as Langhans’ findings demonstrate convincingly that the Treg compartment in HCV infected livers is heterogeneous, and more detailed analysis, both phenotypically as well as functionally is urgently needed to elucidate the importance of FoxP3+ Treg in disease progression in the inflamed liver. The studies of HJ and AB are supported by the Virgo consortium, funded by the Dutch government project number FES0908, and by the Netherlands Genomics Initiative (NGI) project number 050-060-452. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

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