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Type I interferons maintain Foxp3 expression and T-regulatory cell functions under inflammatory conditions in mice.

ABSTRACT: Foxp3(+) T-regulatory cells (Tregs) maintain intestinal homeostasis under conditions of continuous challenge with inflammatory microbes. However, plasticity of the Treg population under certain conditions has been reported; Foxp3(+) Tregs can be converted to Foxp3(-) CD4(+) T cells.We used mice with a T cell-induced colitis model to study the regulatory role of type I interferons (IFNs) in adaptive immunity. We transferred CD4(+)CD45RB(hi) (RB(hi)) T cells, with or without CD4(+)CD45RB(lo) CD25(+) T cells, from wild-type or IFN-??R(-/-) mice into Rag1(-/-) recipients. We analyzed induction of colitis by flow cytometry, confocal microscopy, and enzyme-linked immunosorbent assay and reverse-transcription polymerase chain reaction analyses. IFN-??R(-/-)Rag(-/-) mice were given injections of recombinant IFN-? following transfer of IFN-??R(-/-) RB(hi) T cells and CD4(+)Foxp3(+) cells from Foxp3-eGFP mice.Signaling by type I IFNs was required for maintenance of Foxp3 expression and the suppressive activity of Tregs in mice. Transfer of CD4(+)CD45RB(lo)CD25(+) Tregs from IFN-??R(-/-) mice did not prevent T-cell induction of colitis in mice. Foxp3 expression by Tregs transferred from IFN-??R(-/-) mice was significantly lower than that of Tregs from wild-type mice. Administration of recombinant IFN-? reduced T cell-mediated colitis by increasing the number of Foxp3(+) Tregs and their suppressive functions.Type I IFNs regulate intestinal homeostasis by maintaining Foxp3 expression on Tregs in colons of mice under inflammatory conditions.

SUBMITTER: Lee SE

PROVIDER: S-EPMC3729390 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Type I interferons maintain Foxp3 expression and T-regulatory cell functions under inflammatory conditions in mice.

Lee Shee Eun SE Li Xiangli X Kim Joanna C K JC Lee Jongdae J González-Navajas Jose M JM Hong Seol Hee SH Park In-Kyu IK Rhee Joon Haeng JH Raz Eyal E

Gastroenterology 20120401 1

<h4>Background & aims</h4>Foxp3(+) T-regulatory cells (Tregs) maintain intestinal homeostasis under conditions of continuous challenge with inflammatory microbes. However, plasticity of the Treg population under certain conditions has been reported; Foxp3(+) Tregs can be converted to Foxp3(-) CD4(+) T cells.<h4>Methods</h4>We used mice with a T cell-induced colitis model to study the regulatory role of type I interferons (IFNs) in adaptive immunity. We transferred CD4(+)CD45RB(hi) (RB(hi)) T cel ...[more]

PMID: 22475534

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Project description:Background & aimsHepatitis C virus (HCV) is difficult to eradicate and type III interferons (IFN-?, composed of IL-28A, IL-28B and IL-29) are novel therapeutic candidates. We hypothesized that IFN-? have immunomodulatory effects in HCV- infected individuals.Materials and methodsWe analyzed the expression of IFN-? and its receptor (composed of IL-10R2 and IFN-?R subunits) in the blood and livers of patients with chronic (c)HCV infection compared to controls (those who cleared HCV by sustained virological response, SVR, and those with liver inflammation of non-viral origin, non-alcoholic steatohepatitis, NASH). We also compared the proliferative capacity of dendritic cells (DCs) obtained from healthy individuals and those with chronic HCV using a mixed leukocyte reaction combined with 3H-Td incorporation. In addition, the composition of the IFN-? receptor (IFN-?R) on myeloid DCs, plasmacytoid DCs, PBMCs, and T cells was determined by FACS analysis.ResultsWe report that the expression of IFN-? protein in serum and mRNA in liver is increased in cHCV patients, but not in those with HCV SVR or NASH, compared to controls. Liver level of IFN-?R mirrored the expression of serum IFN-? and was higher in cHCV, compared to controls and HCV-SVR patients, suggesting that elevation of IFN-? and IFN-?R are HCV-dependent. We further identified that innate immune cell populations expressed complete IFN-? receptor. In vitro, recombinant IFN-? promoted differentiation of monocyte-derived dendritic cells (DCs) into a phenotype with low T cell stimulatory capacity and high PD-L1 expression, which further promoted expansion of existing regulatory T cells. IFN-?-DCs failed to induce de novo generation of regulatory T cells. The inhibitory capacity of IFN-?-DCs was counteracted by recombinant IL-12 and by neutralization of the PD-1/PD-L1 system.ConclusionsOur novel findings of the immunomodulatory effect of IFN-? contribute to the understanding of the anti-inflammatory and/or anti-viral potential of IFN-? in cHCV.

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Type I interferons maintain Foxp3 expression and T-regulatory cell functions under inflammatory conditions in mice.

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Type I interferons maintain Foxp3 expression and T-regulatory cell functions under inflammatory conditions in mice.

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