Molecular control of regulatory T cells by NFIL3

Regulatory T (Treg) cells constitute on average 12% of human peripheral blood mononuclear cells (PBMCs) and are characterized by their capacity to suppress T cell proliferation. Treg cells play an important role in T cell homeostasis and are critical regulators of immune tolerance. Deficiencies of Treg cells have been suggested to contribute to the development of autoimmune diseases. Nevertheless, the exact mechanism(s) of how Treg cells exert their regulatory function is still under debate. The forkhead family transcription factor (Foxp3) is a key master transcription factor (TF) that promotes the regulatory phenotype. Foxp3 was found to be necessary for the development but also for the function of Treg cells. The capacity to suppress polarized settings is associated with the acquisition of specific TF. Our preliminary data show an upregulation of the TF NFIL3 in Th2 polarizing conditions. The basic leucine zipper transcription factor nuclear factor IL- 3-regulated (NFIL3 or E4BP4) has been shown to play a role in a range of immunological processes. NFIL3 was originally described to be necessary for the development of bone marrow-derived natural killer cells and macrophages but is also involved in the development and the functions of other immune cells. In CD4 + T cells, it could be demonstrated that NFIL3 regulates production of various cytokines. However, the exact role of NFIL3 in Treg cells have not been explored yet. We therefore plan to address the regulation of NFIL3 in regulatory T cells. Using NFIL3 deficient mice will further allow to define the contribution of NFIL3 for the development and function of Treg cells. Transcriptomic analyses aim to define the exact role of NFIL3 as a transcriptional activator or repressor on a genomewide scale. Experiments are designed to investigate whether Treg specific deletion of NFIL3 leads to an enhanced inflammatory phenotype under homeostatic conditions and within a Th2 disease (asthma) model in vivo. A better understanding of the mechanism, which are necessary to maintain tolerance will ultimately lead to new treatment strategies to control autoimmunity and inflammatory diseases.