Regulatory T (Treg) cells are the primary mediators of peripheral tolerance and their alteration is one of the major causes of autoimmune disorders. Treg cells develop in the thymus (natural (n)Treg cells) or are formed from conventional CD4+ T cells in the periphery in specific conditions (adaptive or induced (i)Treg cells). The transcriptio factor Foxp3 is crucial for Treg cell development and function, and mutations at the Foxp3 locus cause lymphoproliferative disorders associated with fatal inflammation, both in humans and mice. Foxp3 expression in nTreg and iTreg cells is controlled by several conserved noncoding sequences (CNS) at the Foxp3 locus. Deciphering how expression of Foxp3 is regulated and maintained in Treg cells, what transcription factors regulate its expression and how they modulate chromatin at Foxp3 locus, are imperative questions critical for understanding Treg cell stability and protection from autoimmunity. Our preliminary results show that Treg cells generated in the absence of the transcription factor Bcl11b express reduced levels of Foxp3, increased proinflammatory cytokines, have reduced suppressive function, and mice with Bcl11b-/- Treg cells develop inflammatory bowel diseases (IBD). Additionally, induction of Foxp3 and generation of iTreg cells from conventional CD4+ T cells are reduced in the absence of Bcl11b. We found that Bcl11b binds Foxp3 promoter, as well as CNS1 and CNS2. Here we propose studies to decipher the mechanisms by which Bcl11b controls expression of Foxp3 in Treg populations, as well as how this influences Treg cell stability. The proposed studies have a major significance in a field of high relevance, namely Treg stability and epigenetic control of Foxp3 expression and also have high relevance for autoimmune diseases, particularly for IBD.
T regulatory (Treg) cells are the primary mediators of peripheral tolerance and their alteration is one of the major causes of autoimmune disorders. This grant application aims to decipher mechanisms implicated in maintenance of stability of these cells, which is critical for development of strategies protective against autoimmunity, including inflammatory bowel disease.
|Uddin, Mohammad N; Zhang, Yubin; Harton, Jonathan A et al. (2014) TNF-?-dependent hematopoiesis following Bcl11b deletion in T cells restricts metastatic melanoma. J Immunol 192:1946-53|
|Avram, Dorina; Califano, Danielle (2014) The multifaceted roles of Bcl11b in thymic and peripheral T cells: impact on immune diseases. J Immunol 193:2059-65|