Identifying the role of transcription regulator Id2 in plasticity of regulatory T cells

Abstract

Regulatory T (Treg) cells, a distinct subset of CD4+ T cells that are essential for maintaining immunological self-tolerance and homeostasis. The transcription factor forkhead box P3 (Foxp3) has been known as a lineage-determining factor of Treg cells and its constitutive expression is required for stability and function of Treg cells. Treg plasticity has been observed in diverse autoimmune conditions leads to the loss of Foxp3 in Treg cells, and their conversion to ‘ex-Foxp3 TH17 cells’, which express pathogenic inflammatory cytokines IL-17A, IL-17F and IL-22, accumulate in sites of inflammation and aggravate autoimmune diseases. Whether an active mechanism drives the generation of these pathogenic ‘exFoxp3 TH17’ cells remains unclear. Here we showed 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 leads to severely reduced Treg compartment and 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. In summary, our results demonstrate that Treg lineage plasticity may be mediated by enhanced expression of another transcription regulator, Id2, which suppresses transcription of Foxp3 to alter Treg lineage stability. Conclusively, we propose therefore that Id2 is one such molecule that can serve as an attractive target likely to be modulated to implement therapeutic modalities for Treg related diseases in the context of autoimmunity as well as cancer.