Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs

Xuexian O. Yang; Roza Nurieva; Gustavo J. Martinez; Hong Soon Kang; Yeonseok Chung; Bhanu P. Pappu; Bhavin Shah; Seon Hee Chang; Kimberly S. Schluns; Stephanie S. Watowich; Xin Hua Feng; Anton M. Jetten; Chen Dong

doi:10.1016/j.immuni.2008.05.007

Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs

Xuexian O. Yang, Roza Nurieva, Gustavo J. Martinez, Hong Soon Kang, Yeonseok Chung, Bhanu P. Pappu, Bhavin Shah, Seon Hee Chang, Kimberly S. Schluns, Stephanie S. Watowich, Xin Hua Feng, Anton M. Jetten, Chen Dong

Immunology

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

959 Scopus citations

Abstract

Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3⁺ Treg cells was associated in immune responses. Although TGF-β receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORγt and RORα. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3⁺ Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORγ, and RORα were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.

Original language	English (US)
Pages (from-to)	44-56
Number of pages	13
Journal	Immunity
Volume	29
Issue number	1
DOIs	https://doi.org/10.1016/j.immuni.2008.05.007
State	Published - Jul 18 2008

Keywords

CELLIMMUNO
MOLIMMUNO

ASJC Scopus subject areas

Immunology and Allergy
Immunology
Infectious Diseases

MD Anderson CCSG core facilities

Flow Cytometry and Cellular Imaging Facility
Genetically Engineered Mouse Facility
Research Animal Support Facility

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10.1016/j.immuni.2008.05.007

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@article{0a86b9eaff4549cc9ef791dc17b60a7e,

title = "Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs",

abstract = "Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3+ Treg cells was associated in immune responses. Although TGF-β receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORγt and RORα. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3+ Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORγ, and RORα were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.",

keywords = "CELLIMMUNO, MOLIMMUNO",

author = "Yang, {Xuexian O.} and Roza Nurieva and Martinez, {Gustavo J.} and Kang, {Hong Soon} and Yeonseok Chung and Pappu, {Bhanu P.} and Bhavin Shah and Chang, {Seon Hee} and Schluns, {Kimberly S.} and Watowich, {Stephanie S.} and Feng, {Xin Hua} and Jetten, {Anton M.} and Chen Dong",

note = "Funding Information: We thank A. Rudensky and R. Medzhitov for the Foxp3-GFP reporter mice, E. Robertson for Smad4 fl/fl mice, R. Tsien and R. Flavell for the mRFP cDNA, E. Wieder and Y. Wan for help on FACS sorting and analysis, K. Murphy for RV-GFP vector, and the members of the Dong lab for their help. The work is supported by research grants from the National Institutes of Health (NIH; AR050772 to C.D. and CA108454 to X.H.F.), an Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS, NIH) (to A.M.J.), and the MD Anderson Cancer Center and the Gillson Longenbaugh Foundation (to S.S.W.). R.N. is the recipient of a Scientist Development Grant from the American Heart Association. X.H.F. and C.D. are Leukemia & Lymphoma Society Scholars. K.S. and C.D. are both Trust Fellows of the MD Anderson Cancer Center. C.D. is a Cancer Research Institute Investigator and an American Lung Association Career Investigator. ",

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doi = "10.1016/j.immuni.2008.05.007",

language = "English (US)",

volume = "29",

pages = "44--56",

journal = "Immunity",

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T1 - Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs

AU - Yang, Xuexian O.

AU - Nurieva, Roza

AU - Martinez, Gustavo J.

AU - Kang, Hong Soon

AU - Chung, Yeonseok

AU - Pappu, Bhanu P.

AU - Shah, Bhavin

AU - Chang, Seon Hee

AU - Schluns, Kimberly S.

AU - Watowich, Stephanie S.

AU - Feng, Xin Hua

AU - Jetten, Anton M.

AU - Dong, Chen

N1 - Funding Information: We thank A. Rudensky and R. Medzhitov for the Foxp3-GFP reporter mice, E. Robertson for Smad4 fl/fl mice, R. Tsien and R. Flavell for the mRFP cDNA, E. Wieder and Y. Wan for help on FACS sorting and analysis, K. Murphy for RV-GFP vector, and the members of the Dong lab for their help. The work is supported by research grants from the National Institutes of Health (NIH; AR050772 to C.D. and CA108454 to X.H.F.), an Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS, NIH) (to A.M.J.), and the MD Anderson Cancer Center and the Gillson Longenbaugh Foundation (to S.S.W.). R.N. is the recipient of a Scientist Development Grant from the American Heart Association. X.H.F. and C.D. are Leukemia & Lymphoma Society Scholars. K.S. and C.D. are both Trust Fellows of the MD Anderson Cancer Center. C.D. is a Cancer Research Institute Investigator and an American Lung Association Career Investigator.

PY - 2008/7/18

Y1 - 2008/7/18

N2 - Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3+ Treg cells was associated in immune responses. Although TGF-β receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORγt and RORα. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3+ Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORγ, and RORα were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.

AB - Regulatory T (Treg) and T helper 17 (Th17) cells were recently proposed to be reciprocally regulated during differentiation. To understand the underlying mechanisms, we utilized a Th17 reporter mouse with a red fluorescent protein (RFP) sequence inserted into the interleukin-17F (IL-17F) gene. Using IL-17F-RFP together with a Foxp3 reporter, we found that the development of Th17 and Foxp3+ Treg cells was associated in immune responses. Although TGF-β receptor I signaling was required for both Foxp3 and IL-17 induction, SMAD4 was only involved in Foxp3 upregulation. Foxp3 inhibited Th17 differentiation by antagonizing the function of the transcription factors RORγt and RORα. In contrast, IL-6 overcame this suppressive effect of Foxp3 and, together with IL-1, induced genetic reprogramming in Foxp3+ Treg cells. STAT3 regulated Foxp3 downregulation, whereas STAT3, RORγ, and RORα were required for IL-17 expression in Treg cells. Our data demonstrate molecular antagonism and plasticity of Treg and Th17 cell programs.

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KW - MOLIMMUNO

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DO - 10.1016/j.immuni.2008.05.007

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AN - SCOPUS:46749138596

SN - 1074-7613

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ER -

Molecular Antagonism and Plasticity of Regulatory and Inflammatory T Cell Programs

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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