SNORD104 microRNA · SNORD104 gene-encoded microRNA and its role in immune homeostasis

MicroRNAs constitute an essential, evolutionary conserved mechanism of posttranscriptional gene expression regulation and thereby affect almost all biological processes including immune functions. In a comprehensive small RNA profiling study we identified a new, Snord104-derived microRNA, miR-145561, which is highly expressed in activated mature lymphocytes. To investigate the role of this lymphocyte-predominant microRNA we generated miR-145561 knockout mice. Aging miR-145561-deficient mice present with splenomegaly and lymphadenopathy and show an increased frequency of germinal center B cells and memory CD4 T cells. In vitro, miR-145561-deficient B cells and T cells are hyper-responsive to innate and adaptive immune receptor stimulation. In addition, miR-145561-deficient T cells show a propensity to differentiate into IL-17 producing cells. These preliminary data strongly suggest that miR-145561 plays an essential role in immune homeostasis through its function as a non-redundant negative regulator of innate and adaptive immune receptor signaling in mature lymphocytes.The goal of the current research proposal is to investigate the function of miR-145561 in immune homeostasis and lymphocyte function through the following experimental strategy: I) identification, validation and functional evaluation of miR-145561 targets in lymphocytes; II) examination of adaptive immune responses to T cell-dependent and T cell-independent antigens in miR-145561-deficient and -proficient mice; III) investigation of the susceptibility of miR-145561-deficient mice to spontaneous autoimmunity and how miR-145561-definciency affects disease onset and severity in autoimmunity prone mice; and IV) to investigate the function of the human miR-145561 homolog.This project sheds light into the mechanisms by which microRNAs regulate immune homeostasis and contribute to the understanding of the pathogenesis of autoimmune diseases and other inflammatory disorders.