Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis

Rodrigo Liberal; Charlotte R. Grant; Muhammed Yuksel; Jonathon Graham; Alireza Kalbasi; Yun Ma; Michael A. Heneghan; Giorgina Mieli-Vergani; Diego Vergani; Maria Serena Longhi

doi:10.1002/hep.29307

Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis

Rodrigo Liberal, Charlotte R. Grant, Muhammed Yuksel, Jonathon Graham, Alireza Kalbasi, Yun Ma, Michael A. Heneghan, Giorgina Mieli-Vergani, Diego Vergani, Maria Serena Longhi^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

43 Citations (Scopus)

Abstract

Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4⁺CD127⁺CD25^high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood–derived CD4⁺CD127⁺ CD25^high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4⁺CD127⁺CD25^high cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4⁺CD127⁺CD25^high cells obtained from CD4⁺ cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4⁺CD127⁺CD25^high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. Conclusion: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570–1584).

Original language	English
Pages (from-to)	1570-1584
Number of pages	15
Journal	Hepatology
Volume	66
Issue number	5
Early online date	3 Oct 2017
DOIs	https://doi.org/10.1002/hep.29307
Publication status	Published - 1 Nov 2017

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@article{3e506cd06650440e83035e10d0140b9f,

title = "Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis",

abstract = "Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4+CD127+CD25high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood–derived CD4+CD127+ CD25high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4+CD127+CD25high cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4+CD127+CD25high cells obtained from CD4+ cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4+CD127+CD25high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. Conclusion: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570–1584).",

author = "Rodrigo Liberal and Grant, {Charlotte R.} and Muhammed Yuksel and Jonathon Graham and Alireza Kalbasi and Yun Ma and Heneghan, {Michael A.} and Giorgina Mieli-Vergani and Diego Vergani and Longhi, {Maria Serena}",

year = "2017",

month = nov,

day = "1",

doi = "10.1002/hep.29307",

language = "English",

volume = "66",

pages = "1570--1584",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Wolters Kluwer Health",

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TY - JOUR

T1 - Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis

AU - Liberal, Rodrigo

AU - Grant, Charlotte R.

AU - Yuksel, Muhammed

AU - Graham, Jonathon

AU - Kalbasi, Alireza

AU - Ma, Yun

AU - Heneghan, Michael A.

AU - Mieli-Vergani, Giorgina

AU - Vergani, Diego

AU - Longhi, Maria Serena

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4+CD127+CD25high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood–derived CD4+CD127+ CD25high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4+CD127+CD25high cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4+CD127+CD25high cells obtained from CD4+ cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4+CD127+CD25high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. Conclusion: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570–1584).

AB - Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4+CD127+CD25high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood–derived CD4+CD127+ CD25high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL-17) production as well as by high levels of T-bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4+CD127+CD25high cells are unresponsive to low-dose IL-2 and in patients have marked proliferative ability, further enhanced by stimulation with IL-7. CD4+CD127+CD25high cells obtained from CD4+ cells exposed to Treg polarizing conditions display enhanced IL-10 production; up-regulate CD49b and LAG-3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL-17. The suppressive function of CD4+CD127+CD25high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. Conclusion: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570–1584).

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U2 - 10.1002/hep.29307

DO - 10.1002/hep.29307

M3 - Article

C2 - 28597951

AN - SCOPUS:85032631939

SN - 0270-9139

VL - 66

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EP - 1584

JO - Hepatology

JF - Hepatology

IS - 5

ER -

Regulatory T-cell conditioning endows activated effector T cells with suppressor function in autoimmune hepatitis/autoimmune sclerosing cholangitis

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