Bcl11b prevents fatal autoimmunity by promoting T _reg cell program and constraining innate lineages in T _reg cells

Abstract

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.

Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

“…Loss of FoxP3 (even slight reductions) often results in generation of exTregs [ 29 , 30 ], while conversion into Teff with unaltered FoxP3 expression is called Treg “fragility” [ 31 ]. Several factors appear to be important for Treg stability/fragility, including IL-2/STAT5 signals [ 11 , 28 , 32 ], Pten/Akt/Foxo1/3a pathway [ 33 , 34 ], autophagy [ 35 ], CARMA1–BCL10–MALT1 (CBM) signalosome complex [ 36 ], Ezh2 [ 37 ], Bcl11b [ 38 ], Eos [ 39 ], PP2A [ 40 ], and Nrp1 [ 31 ]. While the former six pathways are required to stabilize FoxP3, ablation of the latter three factors does not affect FoxP3 expression.…”

Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

“…Upon disruption of CBM, the majority of TI-Tregs produce IFN-γ, followed by stunted tumour growth [ 70 ]. Treg-specific deletion of Bcl11b showed decreased functional marker levels under homeostatic conditions, during inflammation, and in tumours [ 134 ]. Additionally, genome-wide occupancy studies coupled with gene expression profiling revealed that Bcl11b, in association with Foxp3, is critical for establishing a Treg-specific gene activation programme.…”

Bcl11b/Ctip2 in Skin, Tooth, and Craniofacial System

“…Its role in the formation of specific T-cell subsets at different stages of T-cell development and maturation was further investigated. Bcl11b was shown to be required for the development of γδ T-cells ( Shibata et al, 2014 ; Hatano et al, 2017 ; Dolens et al, 2020 ), iNKT cells and T-regulatory cells ( Albu et al, 2011 ; Vanvalkenburgh et al, 2011 ; Uddin et al, 2016 ; Drashansky et al, 2019 ; Hasan et al, 2019 ). Additionally, Bcl11b is involved in the differentiation of CD4 + CD8- helper T cells and CD4-CD8 + cytotoxic T cells through the regulation of key transcription factors ThPOK and Runx3 ( Kojo et al, 2017 , 2018 ).…”

“…Studies on the role of Bcl11b in Treg cells of both humans and mice identified more than 500 targets for Bcl11b. Interestingly, the top 2 enriched motifs for Bcl11b binding were Ets and Runx binding motifs ( Drashansky et al, 2019 ; Hasan et al, 2019 ). Similarly, more than 900 and 94 Bcl11b targets were observed in pro-T cells and ILC2 cells, respectively ( Hosokawa et al, 2020 ).…”

“…In this context, distinct Bcl11b protein partners and different sets of genes controlled by Bcl11b were observed in pro-T and ILC2 cells, indicating that the same transcription factors can regulate substantially different target genes in the two different cells ( Hosokawa et al, 2018 , 2020 ). The results obtained in Treg cells indicated that Bcl11b, in association with Foxp3, is primarily responsible in establishing a Treg-specific gene activation program ( Drashansky et al, 2019 ). Removal of Bcl11b in Treg cells resulted in multiorgan fatal autoimmunity and lymphadenopathy ( Drashansky et al, 2019 ; Hasan et al, 2019 ).…”