Interleukin-12 converts Foxp3+ regulatory T cells to interferonγ-producing Foxp3+ T cells that inhibit colitis

Ting Feng, Anthony T. Cao, Casey T. Weaver, Charles O. Elson, Yingzi Cong

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Background & Aims: Regulatory T (Treg) cells are plastic, but the in vivo mechanisms by which they are converted into foxhead box p3 (Foxp3 +) interferon (IFN)-γ+ T cells and whether these converted cells retain the ability to inhibit colitis are not clear. Methods: Foxp3+ Treg cells were generated by culture of nave CD4+ T cells from Foxp3GFP CBir1 T-cell receptor (TCR) transgenic (Tg) (CBir1-Tg) mice, which are specific for CBir1 flagellin (an immunodominant microbiota antigen), with transforming growth factor-β. Foxp3 GFP+ CBir1-Tg Treg cells were isolated by fluorescence-activated cell sorting and transferred into TCRβxδ-/- mice. Colitis was induced by transfer of nave CBir1-Tg CD4+ T cells into immunodeficient mice. Results: Microbiota antigen-specific Foxp3+ Treg cells were converted, in the intestine, to IFN-γ+ T-helper (Th)1 cells, interleukin (IL)-17+ Th17 cells, and Foxp3+ T cells that coexpress IFN-γ and/or IL-17. Conversion of Treg cells into IFN-γ-producing Th1 cells and Foxp3+IFN-γ+ T cells required innate cell production of IL-12 in the intestine; blocking IL-12 with an antibody inhibited their conversion to Th1 and Foxp3+IFN- γ+ T cells in the intestines of mice that were recipients of Treg cells. Addition of IL-12, but not IL-23, promoted conversion of Treg cells into Th1 and Foxp3+IFN-γ+ T cells, in vitro. Foxp3+IFN-γ+ T cells had regulatory activity because they suppressed proliferation of nave T cells, in vitro, and inhibited induction of colitis by microbiota antigen-specific T cells. IFN-γ+ Th1 cells were not converted into Treg cells; Foxp3 +IFN-γ+ T cells differentiated into IFN-γ+ but not Foxp3+ T cells. Conclusions: IL-12 promotes conversion of Treg cells into IFN-γ-expressing cells; Foxp3 +IFN-γ+ T cells retain their regulatory functions and develop during the transition of Foxp3+ Treg cells into IFN-γ+ Th1 cells.

Original languageEnglish (US)
Pages (from-to)2031-2043
Number of pages13
JournalGastroenterology
Volume140
Issue number7
DOIs
StatePublished - Jun 2011

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Regulatory T-Lymphocytes
Colitis
Interleukin-12
Interferons
T-Lymphocytes
Th1 Cells
Microbiota
Intestines
Interleukin-17
Interleukin-23
Th17 Cells
Antigens
Immunodominant Epitopes
Transforming Growth Factors
T-Cell Antigen Receptor
Transgenic Mice
Plastics
Flow Cytometry

Keywords

  • IBD
  • Immune Regulation
  • Inflammation
  • Inflammatory Bowel Disease
  • Treg

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Interleukin-12 converts Foxp3+ regulatory T cells to interferonγ-producing Foxp3+ T cells that inhibit colitis. / Feng, Ting; Cao, Anthony T.; Weaver, Casey T.; Elson, Charles O.; Cong, Yingzi.

In: Gastroenterology, Vol. 140, No. 7, 06.2011, p. 2031-2043.

Research output: Contribution to journalArticle

Feng, Ting ; Cao, Anthony T. ; Weaver, Casey T. ; Elson, Charles O. ; Cong, Yingzi. / Interleukin-12 converts Foxp3+ regulatory T cells to interferonγ-producing Foxp3+ T cells that inhibit colitis. In: Gastroenterology. 2011 ; Vol. 140, No. 7. pp. 2031-2043.
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abstract = "Background & Aims: Regulatory T (Treg) cells are plastic, but the in vivo mechanisms by which they are converted into foxhead box p3 (Foxp3 +) interferon (IFN)-γ+ T cells and whether these converted cells retain the ability to inhibit colitis are not clear. Methods: Foxp3+ Treg cells were generated by culture of nave CD4+ T cells from Foxp3GFP CBir1 T-cell receptor (TCR) transgenic (Tg) (CBir1-Tg) mice, which are specific for CBir1 flagellin (an immunodominant microbiota antigen), with transforming growth factor-β. Foxp3 GFP+ CBir1-Tg Treg cells were isolated by fluorescence-activated cell sorting and transferred into TCRβxδ-/- mice. Colitis was induced by transfer of nave CBir1-Tg CD4+ T cells into immunodeficient mice. Results: Microbiota antigen-specific Foxp3+ Treg cells were converted, in the intestine, to IFN-γ+ T-helper (Th)1 cells, interleukin (IL)-17+ Th17 cells, and Foxp3+ T cells that coexpress IFN-γ and/or IL-17. Conversion of Treg cells into IFN-γ-producing Th1 cells and Foxp3+IFN-γ+ T cells required innate cell production of IL-12 in the intestine; blocking IL-12 with an antibody inhibited their conversion to Th1 and Foxp3+IFN- γ+ T cells in the intestines of mice that were recipients of Treg cells. Addition of IL-12, but not IL-23, promoted conversion of Treg cells into Th1 and Foxp3+IFN-γ+ T cells, in vitro. Foxp3+IFN-γ+ T cells had regulatory activity because they suppressed proliferation of nave T cells, in vitro, and inhibited induction of colitis by microbiota antigen-specific T cells. IFN-γ+ Th1 cells were not converted into Treg cells; Foxp3 +IFN-γ+ T cells differentiated into IFN-γ+ but not Foxp3+ T cells. Conclusions: IL-12 promotes conversion of Treg cells into IFN-γ-expressing cells; Foxp3 +IFN-γ+ T cells retain their regulatory functions and develop during the transition of Foxp3+ Treg cells into IFN-γ+ Th1 cells.",
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T1 - Interleukin-12 converts Foxp3+ regulatory T cells to interferonγ-producing Foxp3+ T cells that inhibit colitis

AU - Feng, Ting

AU - Cao, Anthony T.

AU - Weaver, Casey T.

AU - Elson, Charles O.

AU - Cong, Yingzi

PY - 2011/6

Y1 - 2011/6

N2 - Background & Aims: Regulatory T (Treg) cells are plastic, but the in vivo mechanisms by which they are converted into foxhead box p3 (Foxp3 +) interferon (IFN)-γ+ T cells and whether these converted cells retain the ability to inhibit colitis are not clear. Methods: Foxp3+ Treg cells were generated by culture of nave CD4+ T cells from Foxp3GFP CBir1 T-cell receptor (TCR) transgenic (Tg) (CBir1-Tg) mice, which are specific for CBir1 flagellin (an immunodominant microbiota antigen), with transforming growth factor-β. Foxp3 GFP+ CBir1-Tg Treg cells were isolated by fluorescence-activated cell sorting and transferred into TCRβxδ-/- mice. Colitis was induced by transfer of nave CBir1-Tg CD4+ T cells into immunodeficient mice. Results: Microbiota antigen-specific Foxp3+ Treg cells were converted, in the intestine, to IFN-γ+ T-helper (Th)1 cells, interleukin (IL)-17+ Th17 cells, and Foxp3+ T cells that coexpress IFN-γ and/or IL-17. Conversion of Treg cells into IFN-γ-producing Th1 cells and Foxp3+IFN-γ+ T cells required innate cell production of IL-12 in the intestine; blocking IL-12 with an antibody inhibited their conversion to Th1 and Foxp3+IFN- γ+ T cells in the intestines of mice that were recipients of Treg cells. Addition of IL-12, but not IL-23, promoted conversion of Treg cells into Th1 and Foxp3+IFN-γ+ T cells, in vitro. Foxp3+IFN-γ+ T cells had regulatory activity because they suppressed proliferation of nave T cells, in vitro, and inhibited induction of colitis by microbiota antigen-specific T cells. IFN-γ+ Th1 cells were not converted into Treg cells; Foxp3 +IFN-γ+ T cells differentiated into IFN-γ+ but not Foxp3+ T cells. Conclusions: IL-12 promotes conversion of Treg cells into IFN-γ-expressing cells; Foxp3 +IFN-γ+ T cells retain their regulatory functions and develop during the transition of Foxp3+ Treg cells into IFN-γ+ Th1 cells.

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KW - IBD

KW - Immune Regulation

KW - Inflammation

KW - Inflammatory Bowel Disease

KW - Treg

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