Functional role of the transcription factor NFATc1 in allergic asthma

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Allergic asthma is a chronic inflammatory disease of the airways that affects millions of people world-wide. NFATc1, a member of the nuclear factor of activated T cells (NFAT) transcription factor family, is regulated in cells controlling both innate and adaptive immune responses and contributes to their effector function and cell homeostasis. In previous studies, we analyzed the role of NFATc1 in T cells in a murine model of allergic asthma by using NFATc1fl/fl control mice and NFATc1fl/flxCD4Cre mice after OVA sensitization and challenge. In the last funding period, we extended this observation to a second model of asthma with higher relevance for human allergic asthma induced by House dust mite (HDM) sensitization and challenge and demonstrated that NFATc1 deficiency in T cells results in impaired differentiation of Th2 cells and induction of airway tolerance in allergic asthma. Moreover, in the HDM model of asthma, targeting NFATc1 in CD19+ B cells in the newly generated NFATc1fl/flxCD19Cre resulted in reduced airway hyperresponsiveness and suppressed serum IgE levels. Furthermore, we recently investigated the role of NFAT-interacting protein (NIP)-45, an IL-4 inducing Transcription Factor in the pathogenesis of asthma. NIP45 mRNA was found to be induced in blood cells of asthmatic pre-school children. Targeted deletion of NIP45 in mice resulted in a protective phenotype in models of asthma associated with reduced mucus production and impaired airway hyperresponsiveness. In addition to NFATc1 and NIP45, also NFATc2 was found to be up-regulated in peripheral blood mononuclear cells from asthmatic children and adults with allergic asthma. In conclusion, targeting NFATc in T and B lymphocytes might ameliorate the allergic phenotype in asthmatic subjects.In this grant application, we want to continue to identify the target genes of NFATc1 in murine lung CD4+ T as well as B cells by extending the analysis to the NFATc1-mb-1Cre mice in HDM induced asthma. Moreover, to further investigate the role of NFATc1 in airway tolerance as therapy for asthma, we want to delete NFATc1 in dendritic cells by creating the conditional gene targeting NFATc1fl/flCD11cCre+ mice. Finally, we will study the role of NFATc1 in sorted human DCs, T and B cells isolated from the peripheral blood of control and asthma adult patients in a new clinical study, denoted AZCRA. We then will perform RNA seq to profile gene expression in human DCs, T and B cells respectively. In summary, this project aims to shed light on the role of NFATc1 in T, B and DC cells in allergic asthma in order to design novel therapeutic approaches for this disease.