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

Silvia Piconese, Eleonora Timperi, Ilenia Pacella, Valeria Schinzari, Claudio Tripodo, Massimo Rossi, Nicola Guglielmo, Gianluca Mennini, Gian Luca Grazi, Simona Di Filippo, Stefania Brozzetti, Katia Fazzi, Guido Antonelli, Maria Antonietta Lozzi, Massimo Sanchez, Vincenzo Barnaba

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1494-1507
Number of pages14
JournalHepatology
Volume60
Issue number5
DOIs
Publication statusPublished - Nov 1 2014

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Regulatory T-Lymphocytes
Hepacivirus
Liver
OX40 Ligand
Forkhead Transcription Factors
Phenotype
Neoplasms
Th1 Cells
Chronic Hepatitis C
Interleukin-12
Interferon-gamma
Monocytes
Macrophages
Inflammation
Population

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Piconese, S., Timperi, E., Pacella, I., Schinzari, V., Tripodo, C., Rossi, M., ... Barnaba, V. (2014). Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue. Hepatology, 60(5), 1494-1507. https://doi.org/10.1002/hep.27188

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

In: Hepatology, Vol. 60, No. 5, 01.11.2014, p. 1494-1507.

Research output: Contribution to journalArticle

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 & Barnaba, V 2014, 'Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue', Hepatology, vol. 60, no. 5, pp. 1494-1507. https://doi.org/10.1002/hep.27188
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. / Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue. In: Hepatology. 2014 ; Vol. 60, No. 5. pp. 1494-1507.
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AU - Piconese, Silvia

AU - Timperi, Eleonora

AU - Pacella, Ilenia

AU - Schinzari, Valeria

AU - Tripodo, Claudio

AU - Rossi, Massimo

AU - Guglielmo, Nicola

AU - Mennini, Gianluca

AU - Grazi, Gian Luca

AU - Di Filippo, Simona

AU - Brozzetti, Stefania

AU - Fazzi, Katia

AU - Antonelli, Guido

AU - Lozzi, Maria Antonietta

AU - Sanchez, Massimo

AU - Barnaba, Vincenzo

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N2 - 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.

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