Inflammation-induced Id2 promotes plasticity in regulatory T cells.

Abstract

TH17 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.

• Authors: Sung-Min Hwang, Garima Sharma, Ravi Verma, Seohyun Byun, Dipayan Rudra, Sin-Hyeog Im
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 4736 (11 09 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30413714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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, metabolism)
• Humans
• Immunity
• Inflammation (immunology, 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)