Define the role of REV-ERB in colonic RORgt+ regulatory T cells

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PROJECT SUMMARY Regulatory T cells (Treg) play a crucial role in keeping the immune system in balance and preventing autoimmune disease. Defective Treg function leads to autoimmune diseases, while intra-tumor Tregs can block effective anti-tumor immune responses. Tregs can undergo further specialization in adaptation to their tissue microenvironment. Recent studies showed that a unique RORgt (retinoic acid–related orphan receptor gamma t) expressing Treg cell population could be induced in the colon lamina propria. These RORgt+ Tregs play an important role in the suppression of colon inflammation. In Treg cells, REV-ERBa is highly expressed in RORgt+ colonic Tregs, but not in RORgt- colonic Tregs or spleen Tregs. Mice with Treg-specific deletion of REV-ERB were more susceptible to TNBS-induced colitis with decreased RORgt+ Treg cells and increased Th1/Th17 cell- mediated inflammation in the colon. RNA-sequencing experiment showed that the expression of a set of genes related to Treg function, including CTLA-4, IL-10, and c-Maf, were reduced in REV-ERB deficient colonic Tregs compared to WT controls. To study the mechanism of gene regulation by REV-ERB in Tregs, Dr. Zheng’s lab performed Cut & Run assays with WT RORgt+ iTregs using Foxp3, REV-ERBa, and RORgt antibodies to map their binding peaks genome-wide. The results showed a significant overlap of the binding peaks of these 3 transcription factors, suggesting coordination in gene regulation among Foxp3, REV-ERB, and RORgt in Treg cells. The overall objective of the proposed study is to define the role of REV-ERB in Treg function. This goal will be accomplished by dissecting the molecular mechanism of REV-ERB function in RORgt+ Treg cells (Aim 1), and characterizing the role of REV-ERB in Treg in mouse models of IBD (Aim 2). The outcomes of the proposed study are expected to reveal the functional and mechanistic role of REV-ERB in RORgt+ Tregs. Such results are expected to further advance our understanding of how the identity and function of RORgt+ Tregs are established and maintained. Additionally, this study will provide key insights into how transcriptional repressor such as REV- ERB serves as key regulator and tune the function of transcriptional activators in Treg cells. Finally, the outcomes of this study could provide evidence supporting the development of therapeutics targeting REV-ERB for IBD treatment.