This is a proposal to investigate the role of microRNAs in autoimmune diseases. Collectively, 5-10% of the western population is affected by some of the more than 80 autoimmune diseases that arise when the immune system attacks its own body. Current treatment options have limited efficacy, are expensive and have severe side effects such as increased risk for infections and cancer. In the long-term we aim to exploit microRNAs to control the immune system gone awry in patients with autoimmune diseases in order to restore immune homeostasis. Regulatory T cells (Treg) are cells of the immune system specialized to suppress immune responses. Due to their proven ability to prevent and even cure preclinical animal models of autoimmune diseases such as Type 1 diabetes and multiple sclerosis and their important role in preventing rejection of transplanted organs, Treg have entered clinical trials. In contrast, T follicular helper (TFH) cells provide classic """"""""help"""""""" to B clls supporting the B cells'function to produce high-affinity antibodies. Both, dysregulation of Treg o TFH promote autoimmunity. microRNAs are regulators of gene expression only discovered relatively recently. Therefore our understanding of microRNA function in the immune system is very limited. Using in vivo gene ablation we showed the importance of the miRNA cluster miR-17-92 for Treg and TFH function. It is intriguing that miR-17- 92 sustains both, promoters and inhibitors of immune responses, respectively. [An important new finding is that miR-17-92 represses subset-inappropriate gene expression during TFH differentiation. Accordingly, we have refined the experiments to delineate in detail how miR-17-92 regulates T cell differentiation with a particular emphasis on the cell fate decision to differentiate into TFH rather than alternative T cell subsets. We propose that in the absence of miR-17-92 the cells respond to environmental cues they are not supposed to receive. We will characterize in depth the consequences of these inappropriate signals during TFH differentiation which will teach us what the normal function of miR-17-92 is. We will further assess if the same pathways are regulated by miR-17-92 in the functionally opposing Treg cells.] We will use cell culture assays and [mouse models used to generate TFH cells after infection and a model of acute autoimmune disease: experimental autoimmune encephalitis.] We are using mice that lack the miR-17-92 cluster in all T cells including TFH or only in Treg. The revised specific aims of this proposal ar: 1) [Exploring the role of miR-17-92 in sensing cytokines as a basis for cell fate determination] 2) Determine the molecular [basis] of miR-17-92 function in TFH and Treg.

Public Health Relevance

Autoimmune diseases affect 5-10% of the western population and cause tremendous suffering and billions of annual health care costs. We will investigate how genes called microRNAs prevent the development of these debilitating diseases. The proposed experiments [are designed to improve the basic understanding how one particular microRNA locus called the miR-17-92 cluster regulates T cell subsets implicated in the promotion and prevention of autoimmune diseases. We anticipate that the results could] lay the basis for rationale design of a novel class of therapeutics targeting the miR-17-92 cluster.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Rothermel, Annette L
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University Hospital Basel
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Pua, Heather H; Steiner, David F; Patel, Sana et al. (2016) MicroRNAs 24 and 27 Suppress Allergic Inflammation and Target a Network of Regulators of T Helper 2 Cell-Associated Cytokine Production. Immunity 44:821-32
Khan, Imran S; Park, Chong Y; Mavropoulos, Anastasia et al. (2015) Identification of MiR-205 As a MicroRNA That Is Highly Expressed in Medullary Thymic Epithelial Cells. PLoS One 10:e0135440
Jeker, Lukas T; Marone, Romina (2015) Targeting microRNAs for immunomodulation. Curr Opin Pharmacol 23:25-31
Khan, Imran S; Taniguchi, Ruth T; Fasano, Kayla J et al. (2014) Canonical microRNAs in thymic epithelial cells promote central tolerance. Eur J Immunol 44:1313-9