1. Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue
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Gianluca Mennini, Silvia Piconese, Massimo Sanchez, G. Grazi, Guido Antonelli, Vincenzo Barnaba, Massimo Rossi, Ilenia Pacella, Claudio Tripodo, Eleonora Timperi, Stefania Brozzetti, Simona Di Filippo, Katia Fazzi, Maria A ntonietta Lozzi, V. Schinzari, Nicola Guglielmo, Department of Internal Medicine and Medical Specialities, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Università degli studi di Palermo - University of Palermo, Dip di Chirurgia Generale e Trapianti d’Organo - Sapienza Università, Dipartimento di Chirurgia - Sapienza Università, Department of Molecular Medicine, Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], CISDEM-CSIC, Institute of Construction Science 'Eduardo Torreja', Réseau International des Instituts Pasteur (RIIP), 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, AteneoSapienza [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 bygrants 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)., The authors thank Marco Cassatella and Federica Calzetti (Università di Verona) for providing anti‐M‐DC8 antibody, Maria Cristina Gagliardi (Istituto Superiore di Sanità, Rome) for providing anti‐CD206 antibody, Carla Guarnotta (Università di Palermo) for technical assistance in immunohistochemical stainings, and Stefania Morrone ('Sapienza' Università di Roma, Rome) for help with cell sorting. The authors also acknowledge Massimo Locati and Alberto Mantovani for their helpful discussion., Piconese, Silvia, Timperi, Eleonora, Pacella, Ilenia, Schinzari, Valeria, Tripodo, Claudio, Rossi, Massimo, Guglielmo, Nicola, Mennini, Gianluca, Grazi, Gian Luca, Di Filippo, Simona, Brozzetti, Stefania, Fazzi, Katia, Antonelli, Guido, Lozzi, Maria Antonietta, Sanchez, Massimo, Barnaba, Vincenzo, Piconese, S, Timperi, E, Pacella, I, Schinzari, V, Tripodo, C, Rossi, M, Guglielmo, N, Mennini, G, Grazi, GL, Di Filippo, S, Brozzetti, S, Fazzi, K, Antonelli, G, Lozzi, MA, Sanchez, M, and Barnaba, V.
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MESH: Receptors, OX40/metabolism ,MESH: Interleukin-12/metabolism ,Liver Cirrhosis ,Male ,Macrophage ,medicine.disease_cause ,MESH: Carcinoma, Hepatocellular/immunology ,T-Lymphocytes, Regulatory ,MESH: OX40 Ligand/metabolism ,0302 clinical medicine ,MESH: Aged, 80 and over ,MESH: T-Lymphocytes, Regulatory/physiology ,MESH: Up-Regulation ,OX40 ,MESH: Aged ,Aged, 80 and over ,0303 health sciences ,education.field_of_study ,T REG ,MESH: Middle Aged ,Medicine (all) ,MESH: Liver Cirrhosis/immunology ,Liver Neoplasms ,hemic and immune systems ,Middle Aged ,MESH: Liver Neoplasms/immunology ,Phenotype ,Hepatitis C ,Interleukin-12 ,3. Good health ,Up-Regulation ,Liver Neoplasm ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Interleukin 12 ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,medicine.symptom ,MESH: Hepatitis C/immunology ,HEPATITIS C VIRUS ,Human ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Hepatitis C virus ,Liver Cirrhosi ,Population ,Inflammation ,chemical and pharmacologic phenomena ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,OX40 Ligand ,Biology ,MESH: Phenotype ,MESH: Liver Neoplasms/virology ,03 medical and health sciences ,Ikaros Transcription Factor ,Downregulation and upregulation ,Internal medicine ,medicine ,Humans ,MESH: Macrophages/metabolism ,education ,030304 developmental biology ,Aged ,MESH: Humans ,Hepatology ,Macrophages ,MESH: Carcinoma, Hepatocellular/virology ,Receptors, OX40 ,MESH: Ikaros Transcription Factor/metabolism ,MESH: Hepatitis C/complications ,MESH: Male ,OX40 ligand ,Immunology ,MESH: Liver Cirrhosis/virology ,MESH: Female ,030215 immunology - Abstract
International audience; 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-c – " 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-c; T-bet 1 IFN-c 1), 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 1 Treg proliferation and antagonized the differentiation of Th1-like Tregs. However, this signal is counteracted in non-cirrhotic liver tissue (showing various levels of inflammation) by high availability of interleukin-12 and IFN-c, 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)
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- 2014
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