Modulation of immunological processes by KSRP

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The regulation of the functional activities of immune cells requires dynamic rapid adaption of gene expression. In immortalized cell lines, KSRP (KH-type splicing regulatory protein) was reported to limit mRNA stability of cytokine-encoding mRNAs and to mediate microRNA-155 maturation, known to contribute to immune cell regulation. KSRP limited the half-life of type I interferon-encoding genes, and in agreement KSRP-/- mice displayed higher resistance towards viral infection. Our preliminary work indicated that KSRP affects the functional activity of polymorphonuclear neutrophilic granulocytes (PMN) in terms of migratory activity. Moreover, KSRP-/- CD4+ T cells were characterized by an intrinsic T helper cell type 2 (Th2) bias in response to stimulation as confirmed by RNA-Seq and cytokine measurements. In line, KSRP-/- mice presented a milder course of collagen antibody induced-arthritis (CAIA) known to be caused by myeloid and Th1 cells. Similarly, KSRP-/- mice presented an aggravated course in ovalbumin (OVA)-induced asthma Taken together, our results indicate that KSRP constitutes a yet unknown important regulator of immune responses.Our study is aimed to delineate the role of KSRP for the regulation of innate and adaptive immune responses as a prerequisite to envisage KSRP-focused therapeutic approaches. We want to substantiate our preliminary findings concerning the aggravated course of OVA-associated asthma, and elucidate in detail the relative contribution of T cells, B cells and PMN. We will dissect on molecular level by which mechanisms KSRP inhibits expression of Th2-promoting IL-4 in CD4+ T cells, including the identification of important transcription factors and signalling adaptors. In this context, we will also discriminate direct and indirect KSRP target genes in T cells based on our RNA-Seq results. We will dissect both intrinsic and extrinsic (Th2 help) effects of KSRP deficiency on the immunophenotype and function of B cells concerning the character of humoral immune responses. Furthermore, the reasons for enhanced proliferation of KSRP-deficient CD4+ T cells as well as KSRP-mediated regulatory T cell function will be examined. The functional relevance of KSRP for pathogen killing activity of PMN will be monitored in a model of aspergillosis. Furthermore, we will perform rescue experiments in the asthma disease model to substantiate the suitability of KSRP for immunopharmacological intervention. Mice with a cell type-specific KSRP knockout will be generated to confirm key experiments from asthma studies.