【Seminar】Molecular Analysis of NFAT/ICER Repressor Complexes and their Role in nTreg-cell mediated Suppression by Dr. Josef Bodor
Title: Molecular Analysis of NFAT/ICER Repressor Complexes and their Role in nTreg-cell mediated Suppression
Speaker: Dr. Josef Bodor
Biotechnology and Biomedicine Center of the Academy of Sciences and Charles University in Vestec
Inhibition of interleukin-2 (IL-2) gene expression in responder CD4+ T cells is a characteristic feature of naturally occurring CD4+CD25+ Treg (nTreg)-mediated suppression of conventional peripheral CD4+ T cells. Nuclear factor of activated T cells (NFAT) proteins control the expression of the IL-2 gene as well as expression of numerous other genes. We described a strong enhancement of expression of inducible cyclic AMP early repressor (ICER) in CD4+ T cells upon co-culture with nTreg cells suggesting that the transcriptional repressor ICER could play an important role in nTreg mediated suppression. Moreover, we have shown that ICER is expressed in nTregs as well as in suppressed CD4+ T cells. Since ICER can bind in complex with NFAT to composite NFAT/AP-1 sites within the IL-2 promoter, it may be concluded that upon contact with nTregs ICER is decisively involved in the attenuation of IL-2 mRNA expression in nTregs as well as in suppressed CD4+ T cells.
In this project, we will investigate the role of ICER in nTreg-mediated suppression of responder CD4+ T cells. In addition to functional studies on the further characterization of nTreg-mediated suppression through ICER/NFAT complexes in vivo, we plan to determine the structure of protein/protein interaction and DNA-binding domains from ICER and NFAT by X-ray crystallography. The information gained through these structures will be used to map the contact points between the ICER and NFAT proteins whose functional relevance will be tested in vivo. One final goal will be the development of small molecule inhibitors to block the interaction between ICER and NFAT. Such peptides have been successfully developed for the inhibition of calcineurin/NFAT interactions in the past and inhibited the action of NFAT more specifically than cyclosporin. All these studies will provide important information for manipulating nTreg function in human diseases, which are caused by a dysfunction of central tolerance mechanisms.