Investigating the role of the transcription factor Bcl11b in Treg mediated peripheral tolerance

Abstract

Regulatory T (Treg) cells play a pivotal role in maintaining immunological tolerance and hold enormous therapeutic potential in the context of autoimmune diseases and cancer immunotherapy. The suppressive properties of Treg cells rely heavily on robust and stable expression of the transcription factor Foxp3. While it is well established that Foxp3 orchestrates Treg transcriptional program in association with its numerous interacting protein partners, the molecular and phenotypic contributions of many Foxp3-associated proteins remains elusive. One of the most prominent interacting partners of Foxp3 is Bcl11b, which was previously implicated in Treg mediated suppression of intestinal inflammation. However due to its inadequate Treg-specific deletion, precise understanding of Bcl11b’s function in Treg cells remained incompletely understood. We find that efficient Treg-specific deletion of Bcl11b leads to dramatic whole body systemic autoimmunity, which is essentially indistinguishable from that observed in mice with non-functional Foxp3 protein. Mechanistically, by performing genome wide ChIP-seq and RNA-seq analyses in wild type as well as in Foxp3- and Bcl11b-deficient Treg cells, we establish Bcl11b as a core transcriptional component of Treg gene expression program, which in conjugation of Foxp3 largely orchestrates Foxp3 dependent gene activation program. More strikingly we find that Foxp3’s binding intensity and fidelity to a subset of its associated sites is largely altered in the absence of Bcl11b. Additionally, Bcll1b also modulate chromatin accessibility for Foxp3 binding to its associated sites. Together these findings not only provide previously underappreciated basic understanding of the molecular events contributing to Treg homeostasis and function, but also substantially advanced our current understanding of mechanistic aspects of gene expression program in Treg cells and establishes a therapeutic target with potential implications in autoimmunity and cancer.