Generation of RORγt+ Antigen-Specific T Regulatory 17 Cells from Foxp3+ Precursors in Autoimmunity

Byung-Seok Kim; Huiping Lu; Kenji Ichiyama; Xiang Chen; Yi-Bing Zhang; Nipun A Mistry; Kentaro Tanaka; Young-Hee Lee; Roza Nurieva; Li Zhang; Xuexian Yang; Yeonseok Chung; Wei Jin; Seon Hee Chang; Chen Dong

doi:10.1016/j.celrep.2017.09.021

Generation of RORγt⁺ Antigen-Specific T Regulatory 17 Cells from Foxp3⁺ Precursors in Autoimmunity

Cell Rep. 2017 Oct 3;21(1):195-207. doi: 10.1016/j.celrep.2017.09.021.

Authors

Byung-Seok Kim¹, Huiping Lu², Kenji Ichiyama³, Xiang Chen³, Yi-Bing Zhang⁴, Nipun A Mistry⁵, Kentaro Tanaka³, Young-Hee Lee³, Roza Nurieva³, Li Zhang⁶, Xuexian Yang⁷, Yeonseok Chung⁸, Wei Jin², Seon Hee Chang⁹, Chen Dong¹⁰

Affiliations

¹ Department of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA; Laboratory of Immune Regulation, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
² Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
³ Department of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA.
⁴ State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
⁵ Department of Bioinformatics and Computational Biology, MD Anderson Cancer Center, Houston, TX 77054, USA.
⁶ Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45219, USA.
⁷ Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM 87131, USA.
⁸ Laboratory of Immune Regulation, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
⁹ Department of Immunology, MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address: [email protected].
¹⁰ Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].

Abstract

Th17 cells are potent mediators in autoimmune diseases, and RORγt is required for their development. Recent studies have shown that RORγt⁺ Treg cells in the gut regulate intestinal inflammation by inhibiting effector T cell function. In the current study, we report that RORγt⁺ Treg cells were also found in lymph nodes following immunization. Not only distinct from intestinal RORγt⁺ Treg cells in their transcriptomes, peripheral RORγt⁺ Treg cells were derived from Foxp3⁺ thymic Treg cells in an antigen-specific manner. Development of these RORγt⁺ Treg cells, coined T regulatory 17 (Tr17) cells, depended on IL-6/Stat3 signaling. Tr17 cells showed suppressive activity against antigen-specific effector T cells in vitro. In addition, Tr17 cells efficiently inhibited myelin-specific Th17-cell-mediated CNS auto-inflammation in a passive EAE model. Collectively, our study demonstrates that Tr17 cells are effector Treg cells that potentially restrict autoimmunity.

Keywords: Foxp3; IL-17; RORγt; Tr17; Treg; autoimmunity.

MeSH terms

Adoptive Transfer
Animals
Autoimmunity / genetics*
Cell Differentiation
Encephalomyelitis, Autoimmune, Experimental / chemically induced
Encephalomyelitis, Autoimmune, Experimental / genetics*
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / pathology
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / immunology
Gene Expression Regulation
Genes, Reporter
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Inducible T-Cell Co-Stimulator Protein / genetics
Inducible T-Cell Co-Stimulator Protein / immunology
Interleukin-6 / genetics
Interleukin-6 / immunology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Myelin-Oligodendrocyte Glycoprotein / administration & dosage
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics*
Nuclear Receptor Subfamily 1, Group F, Member 3 / immunology
Peptide Fragments / administration & dosage
Receptors, CCR6 / genetics
Receptors, CCR6 / immunology
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / immunology
Signal Transduction
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / pathology
T-Lymphocytes, Regulatory / transplantation
Th17 Cells / immunology*
Th17 Cells / pathology

Substances

CCR6 protein, mouse
Forkhead Transcription Factors
Foxp3 protein, mouse
Icos protein, mouse
Inducible T-Cell Co-Stimulator Protein
Interleukin-6
Myelin-Oligodendrocyte Glycoprotein
Nuclear Receptor Subfamily 1, Group F, Member 3
Peptide Fragments
Receptors, CCR6
STAT3 Transcription Factor
Stat3 protein, mouse
interleukin-6, mouse
myelin oligodendrocyte glycoprotein (35-55)
Green Fluorescent Proteins

Grants and funding

R01 AR050772/AR/NIAMS NIH HHS/United States