miRNA-mediated control of regulatory T cell development and function - a role for miR-181

• Applicant: Professor Dr. Andreas Krueger
• Subject Area: Immunology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 273677971

The adaptive immune system is finely balanced to efficiently fight infectious pathogens on the one hand and to tolerate innocuous antigen as well as self-antigen on the other hand. Disruption of this balance may result in allergy or autoimmune disease. Regulatory T cells (Treg cells) constitute a major tolerogenic T population capable of suppressing an unwanted immune response, whose loss is accompanied by fatal autoimmunity. However, excessive action of Treg cells may also constitute an underlying cause of inefficient immune responses against cancer. Treg cells can be generated in the thymus (nTreg cells) or from naïve cells in the periphery (iTreg cells). The mechanisms controlling development of nTreg cells are only incompletely understood. It has been suggested that nTreg cells are essentially auto-reactive and, therefore, receive TCR signals of different strength and possibly duration. MicroRNAs (miRNAs) are small regulatory RNAs, which function primarily through post-transcriptional repression of a wide variety of target genes. Development and function of Treg cells critically depend on the presence of miRNA. However, the role of individual miRNAs in these processes remains elusive. We have recently shown that miR-181a/b-1 critically controls the generation of invariant natural killer T cells, which follow a very similar developmental pathway as Treg cells. Thus, we hypothesize that miR-181a/b-1 regulates development of nTreg cells. In order to test this hypothesis, we have generated mice deficient in miR-181a/b-1. Employing this novel mouse model we plan to address the following questions in this project: What are the mechanisms by which miR-181a/b-1 controls development of Treg cells? How does miR-181a/b-1 control Treg cell function? Finally, we will complement this proposal by an unbiased approach to identify novel miR-181 target genes. Taken together, this project will shed light on the molecular mechanisms of Treg cell development and function controlled by miRNA. In consequence, our studies might open up new avenues for targeted manipulation of Treg cells to restore the balance between tolerance and autoimmunity in disease.

• DFG Programme: Research Grants