Journal
HEPATOLOGY
Volume 60, Issue 5, Pages 1494-1507Publisher
WILEY-BLACKWELL
DOI: 10.1002/hep.27188
Keywords
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Categories
Funding
- V. B.: Associazione Italiana per la Ricerca sul Cancro (AIRC
- progetto Investigator Grant [IG] [10756]
- European Union (IMECS) [201169]
- European Union (SPHYNX) [261365]
- Ministero della Sanita (Ricerca finalizzata) [RFPS-2006-3-337923, RFPS-2007-1-636647]
- Istituto Superiore di Sanita [Progetto AIDS]
- Ministero dell'Istruzione
- dell'Universita e della Ricerca (MIUR)
- dell'Universita e della Ricerca (Programmi di ricerca di interesse nazionale [PRIN]) [7245/1, 2010LC747T-004]
- Ateneo Sapienza [2009-C26A09PELN, 2010-C26A1029ZS, 2011-C26A11BYWP, 2012-C26A12JL55]
- Fondo per gli investimenti di ricerca di base [FIRB] [RBAP10TPXK]
- Fondazione Cariplo
- FISM (Fondazione Italiana Sclerosi Multipla onlus) [2011/R/4]
- Fondazione Italiana per la Ricerca sull'Artrite (FIRA)
- Istituto Italiano di Tecnologia (IIT)
- Associazione Italiana Ricerca sul Cancro [MFAG 8726]
- Ministero dell'Istruzione, dell'Universita e della Ricerca [RBFR12I3UB_002]
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Regulatory T cells (Tregs) can be considered as a mixed population of distinct subsets, endowed with a diverse extent and quality of adaptation to microenvironmental signals. Here, we uncovered an opposite distribution of Treg expansion, phenotype, and plasticity in different microenvironments in the same organ (liver) derived from patients with chronic hepatitis C: On the one side, cirrhotic and tumor fragments were moderately and highly infiltrated by Tregs, respectively, expressing OX40 and a T-bet(high)IFN-gamma(-)T-helper (Th)1-suppressing phenotype; on the other side, noncirrhotic liver specimens contained low frequencies of Tregs that expressed low levels of OX40 and highly produced interferon-gamma (IFN-gamma; T-bet(+)IFN-gamma(+)), thus becoming Th1-like cells. OX40-expressing and Th1-suppressing Tregs were enriched in the Helios-positive subset, carrying highly demethylated Treg cell-specific demethylated region that configures committed Tregs stably expressing forkhead box protein 3. OX40 ligand, mostly expressed by M2-like monocytes and macrophages, boosted OX40(+) Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in noncirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-gamma, ultimately leading to complete, full Th1-like Treg differentiation. Conclusion: Our data demonstrate that Tregs can finely adapt, or even subvert, their classical inhibitory machinery in distinct microenvironments within the same organ.
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