One of the key features of a functioning immune system is its ability to distinguish antigens of foreign origin from those derived endogenously and to mount an immune response against the former. Antigen response and differentiation of CD4 T cells elicit and orchestrate the initial onset and progression of a wide range of autoimmune diseases. Understanding intrinsic regulations of CD4 T cell function has direct implications for the development of novel therapeutics to treat autoimmune diseases. While the protein-based signal transduction machinery downstream of T cell antigen recognition has been thoroughly studied, we have recently become aware of a novel and crucial element dictating T cell fate microRNA (miRNA). mir-17-92 is a gene cluster that encodes six different miRNAs, whose important roles in tumorigenesis have been well established, however, their impact on T cell regulation and associated molecular mechanisms are almost entirely unknown. Our preliminary studies indicated that this cluster dictates the T cell based autoimmune reaction through a complex mechanism. The objective of this project is to comprehensively dissect the function of mir-17-92 cluster during T cell antigen responses and differentiation. Timely and precise manipulation of these miRNAs should be an effective approach to suppress T cell responsiveness for immune tolerance.
We aim to establish these miRNAs as targets for autoimmune therapy.
In this project, we are focusing on the previously unappreciated roles of miRNAs within miR-17-92 cluster in immunoregulation. The emerging complexity of this oncogenic miRNA cluster calls for detailed functional and mechanistic studies to dissect the individual miRNAs? roles in T cell tolerance. In addition to fundamentally advancing the fields of miRNA biology and T cell biology, this study is very likely to provide new targets and entities for oligonucleotide-based immunotherapy that could regulate T cell efficacy to combat autoimmune diseases.
