Inflammation-induced Id2 promotes plasticity in regulatory T cells

Sung-Min Hwang; Garima Sharma; Ravi Verma; Seohyun Byun; Dipayan Rudra; Sin-Hyeog Im

doi:10.1038/s41467-018-07254-2

Inflammation-induced Id2 promotes plasticity in regulatory T cells

Nat Commun. 2018 Nov 9;9(1):4736. doi: 10.1038/s41467-018-07254-2.

Authors

Sung-Min Hwang^{1

2}, Garima Sharma^{1

2}, Ravi Verma¹, Seohyun Byun^{1

2}, Dipayan Rudra^{3

4}, Sin-Hyeog Im^{5

6

7}

Affiliations

¹ Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, 37673, Republic of Korea.
² Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea.
³ Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, 37673, Republic of Korea. rudrad@ibs.re.kr.
⁴ Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea. rudrad@ibs.re.kr.
⁵ Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, 37673, Republic of Korea. iimsh@postech.ac.kr.
⁶ Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea. iimsh@postech.ac.kr.
⁷ Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea. iimsh@postech.ac.kr.

Abstract

T_H17 cells originating from regulatory T (T_reg) cells upon loss of the T_reg-specific transcription factor Foxp3 accumulate in sites of inflammation and aggravate autoimmune diseases. Whether an active mechanism drives the generation of these pathogenic 'ex-Foxp3 T_H17' cells, remains unclear. Here we show that pro-inflammatory cytokines enhance the expression of transcription regulator Id2, which mediates cellular plasticity of T_reg into ex-Foxp3 T_H17 cells. Expression of Id2 in in vitro differentiated iT_reg cells reduces the expression of Foxp3 by sequestration of the transcription activator E2A, leading to the induction of T_H17-related cytokines. T_reg-specific ectopic expression of Id2 in mice significantly reduces the T_reg compartment and causes immune dysregulation. Cellular fate-mapping experiments reveal enhanced T_reg plasticity compared to wild-type, resulting in exacerbated experimental autoimmune encephalomyelitis pathogenesis or enhanced anti-tumor immunity. Our findings suggest that controlling Id2 expression may provide a novel approach for effective T_reg cell immunotherapies for both autoimmunity and cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmunity
Basic Helix-Loop-Helix Transcription Factors / metabolism
Basic-Leucine Zipper Transcription Factors / metabolism
Cell Differentiation
Cell Line
Cell Lineage
Cell Plasticity*
Forkhead Transcription Factors / genetics
Forkhead Transcription Factors / metabolism
Humans
Immunity
Inflammation / immunology*
Inflammation / pathology
Inhibitor of Differentiation Protein 2 / metabolism*
Interferon Regulatory Factors / metabolism
Interleukin-1beta / metabolism
Interleukin-6 / metabolism
Mice, Inbred C57BL
Mice, Transgenic
Phenotype
Promoter Regions, Genetic / genetics
Protein Binding
STAT3 Transcription Factor / metabolism
Signal Transduction
T-Lymphocytes, Regulatory / immunology*
Th17 Cells / cytology

Substances

Basic Helix-Loop-Helix Transcription Factors
Basic-Leucine Zipper Transcription Factors
Batf protein, mouse
Forkhead Transcription Factors
Foxp3 protein, mouse
Idb2 protein, mouse
Inhibitor of Differentiation Protein 2
Interferon Regulatory Factors
Interleukin-1beta
Interleukin-6
STAT3 Transcription Factor
Tcf3 protein, mouse
interferon regulatory factor-4