Inflammation-induced Id2 promotes plasticity in regulatory T cells

• DOI: 10.1038/s41467-018-07254-2
• Publication Date: 2018-11-05T15:39:13Z
• Authors: Sung-Min Hwang; Garima Sharma; Ravi Verma; Seohyun Byun; Dipayan Rudra; Sin-Hyeog Im
• Keywords: interleukin 1beta; Cell Plasticity; Interleukin-1beta; induced response; experimental autoimmune encephalomyelitis; Autoimmunity; REG CELLS; immune response; ectopic expression; regulatory T lymphocyte; Basic Helix-Loop-Helix Transcription Factors; Promoter Regions, Genetic; Inhibitor of Differentiation Protein 2; Th17 cell; cell fate; 0303 health sciences; cell plasticity; autoimmunity; Mus; Q; Cell Differentiation; Forkhead Transcription Factors; 3. Good health; female; tumor growth; Basic-Leucine Zipper Transcription Factors; Phenotype; Interferon Regulatory Factors; inhibitor of differentiation 2; TH17 CELLS; in vitro study; gene overexpression; lymphocyte differentiation; TUMOR-IMMUNITY; Science; interferon regulatory factor 4; animal experiment; transcription factor FOXP3; T(H)17 CELLS; interleukin 6; Mice, Transgenic; Article; Cell Line; 03 medical and health sciences; STAT3 protein; immune dysregulation; melanoma; cancer; Animals; Humans; controlled study; Cell Lineage; gene; mouse; Inflammation; disease; neuropathology; cancer immunotherapy; nonhuman; doxycycline; Interleukin-6; animal model; Immunity; nucleotide sequence; transcription factor E2A; immunity; tumor immunity; Mice, Inbred C57BL; immune system; inflammation; disease exacerbation; gene expression; cell component; protein

AbstractTH17 cells originating from regulatory T (Treg) cells upon loss of the Treg-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 TH17’ cells, remains unclear. Here we show that pro-inflammatory cytokines enhance the expression of transcription regulator Id2, which mediates cellular plasticity of Treg into ex-Foxp3 TH17 cells. Expression of Id2 in in vitro differentiated iTreg cells reduces the expression of Foxp3 by sequestration of the transcription activator E2A, leading to the induction of TH17-related cytokines. Treg-specific ectopic expression of Id2 in mice significantly reduces the Treg compartment and causes immune dysregulation. Cellular fate-mapping experiments reveal enhanced Treg 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 Treg cell immunotherapies for both autoimmunity and cancer.