Maintaining normal Foxp3+ regulatory T (Treg) cell homeostasis and suppressive function is essential for establishing immunological tolerance. Recently, a class of short regulatory non-coding RNAs also called as microRNAs (miRNAs) are shown to be pivotal in the development and function of Treg cells. Recently we have shown that selectively ablation of miRNAs in Treg cells resulted in the early onset of autoimmune lethality indistinguishable to those that were observed in mice devoid of Treg cells. Distinct miRNA expression profiles, of which many were directly targeted by Foxp3 in Treg cells further suggested specific miRNAs could control different facets of Treg biology. To this end, Foxp3-driven miR-155 is required for maintaining normal Treg cell homeostasis as demonstrated in our previous study. In this application, we have shown that high miR-146a expression in Treg cells is essential for effective controls of TH1 responses through targeting signal transducer and activator transcription 1 (STAT1). Loss of miR-146a in Treg cells resulted in increased levels of both total and phosphorylated STAT1. As a consequence, mice with miR-146a deficient Treg cells succumbed to IFN-?-dependent type I immunopathology. Our current results provided strong evidence suggesting that, in addition to homeostasis in Treg cells, Treg suppression function could also be regulated by a single miRNA. This work further implied that miRNA-dependent post-transcriptional regulation enables Treg cells to control a particular type of effector T cell responses. My previous research involved employing a wide spectrum of molecular and cellular means to study both humoral and cellular immune responses through both a variety of unmanipulated mouse strains and clinical-applicable models including allograft transplantation and different tumor systems. Under Dr. Rudensky's current mentoring and with the rich and resourceful environment provided by Memorial Sloan-Kettering Cancer Center and other members in the Tri-institutional biomedical research community including Weill Cornell Medical College and The Rockefeller University, I propose a multifaceted study employing genetic, biochemical, immunological approaches and whole animal experimentation to examine the role of miRNA-dependent post-transcriptional regulation in Treg cell-mediated immunological tolerance. Together with a comprehensive career development plan, including establishing intra- and inter-institutional collaborations and continued training and education, these elements will undoubtedly facilitate my transition to independent research and should allow me to become a well-established investigator in one of the world's top-research institutes. The proposed studies aim to facilitate basic understanding of miRNA-dependent post-transcriptional regulation in Treg cell biology. Furthermore, the results obtained from these studies will provide critical insights into manipulating Treg cell-mediated suppression as a novel therapeutic approach for transplantation, autoimmune and infectious diseases as well as tumors.
The proposed studies aim to facilitate basic understanding of miRNA-dependent post-transcriptional regulation in Treg cell biology. Furthermore, the results obtained from these studies will provide critical insights into manipulating Treg cell-mediated suppression as a novel therapeutic approach for transplantation, autoimmune and infectious diseases as well as tumors.
|Lu, Li-Fan; Gasteiger, Georg; Yu, I-Shing et al. (2015) A Single miRNA-mRNA Interaction Affects the Immune Response in a Context- and Cell-Type-Specific Manner. Immunity 43:52-64|
|Josefowicz, Steven Z; Lu, Li-Fan; Rudensky, Alexander Y (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531-64|