Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus–infected liver tissue


  • Potential conflict of interest: Prof. Antonelli received grants from Siemens and Vin.

  • This work was supported by the following grants obtained by V.B.: Associazione Italiana per la Ricerca sul Cancro (AIRC; progetto “Investigator Grant” [IG]-2010/13 no. 10756); European Union grants (IMECS no. 201169, FP7-Health-2007-A, and SPHYNX no. 261365, FP7-Health-2010); Ministero della Sanità (Ricerca finalizzata [RFPS-2006-3-337923 and RFPS-2007-1-636647] and Istituto Superiore di Sanità [Progetto AIDS-2008]); Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR; Programmi di ricerca di interesse nazionale [PRIN]-2008/10 no. 7245/1; [PRIN]-2011/13 no. 2010LC747T-004; Ateneo Sapienza [2009-C26A09PELN, 2010-C26A1029ZS, 2011-C26A11BYWP, and 2012-C26A12JL55]; and Fondo per gli investimenti di ricerca di base [FIRB]-2011/13 no. RBAP10TPXK); Fondazione Cariplo (progetti no. 13535 and 3603 2010/12); FISM (Fondazione Italiana Sclerosi Multipla onlus) grant no. 2011/R/4; Fondazione Italiana per la Ricerca sull'Artrite (FIRA 2010); and Istituto Italiano di Tecnologia (IIT; A2 project 2013). This work was also supported by grants obtained by S.P. from Associazione Italiana Ricerca sul Cancro (MFAG 8726) and from Ministero dell'Istruzione, dell'Università e della Ricerca (FIRB-Futuro in ricerca RBFR12I3UB_002).

  • See Editorial on Page 1461


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-bethighIFN-γ “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-γ; T-bet+IFN-γ+), 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-γ, 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. (Hepatology 2014;60:1494–1507)