Bcl11b prevents fatal autoimmunity by promoting Treg cell program and constraining innate lineages in Treg cells.
Theodore T DrashanskyEric Y HelmZhiguang HuoNina B CurkovicPreet KumarXiaoping LuoUpasana ParthasarathyAshley N ZunigaJonathan J ChoKyle J LorentsenZhiwei XuMohammad UddinSafiehkhathoon MoshkaniLiang ZhouDorina AvramPublished in: Science advances (2019)
Regulatory T (Treg) cells are essential for peripheral tolerance and rely on the transcription factor (TF) Foxp3 for their generation and function. Several other TFs are critical for the Treg cell program. We found that mice deficient in Bcl11b TF solely in Treg cells developed fatal autoimmunity, and Bcl11b-deficient Treg cells had severely altered function. Bcl11b KO Treg cells showed decreased functional marker levels in homeostatic conditions, inflammation, and tumors. Bcl11b controlled expression of essential Treg program genes at steady state and in inflammation. Bcl11b bound to genomic regulatory regions of Treg program genes in both human and mouse Treg cells, overlapping with Foxp3 binding; these genes showed altered chromatin accessibility in the absence of Bcl11b. Additionally, Bcl11b restrained myeloid and NK cell programs in Treg cells. Our study provides new mechanistic insights on the Treg cell program and identity control, with major implications for therapies in autoimmunity and cancer.
Keyphrases
- induced apoptosis
- cell cycle arrest
- transcription factor
- oxidative stress
- quality improvement
- immune response
- cell death
- stem cells
- squamous cell carcinoma
- endothelial cells
- signaling pathway
- single cell
- gene expression
- genome wide
- metabolic syndrome
- dna methylation
- pi k akt
- regulatory t cells
- young adults
- cell proliferation
- dendritic cells
- lymph node metastasis
- genome wide analysis