NFAT Transcription Factors Control the Fate of Keratinocytes and Lymphocytes in Skin Homeostasis and Inflammatory Skin Diseases

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Skin homeostasis relies on tightly regulated innate and adaptive immune responses. Immunologic dysbalances at the molecular immunological level can promote inflammatory skin diseases, which are often associated with lymphocytic skin infiltration and consecutive alteration of keratinocyte differentiation.The transcription factors of the NFAT family play an important role in these processes, especially by controlling the activity of T lymphocytes. Using NFATc1- and NFATc2-deficient T-cells in an in vitro keratinocyte/T-cell co-culture model we could recently show that these T cells almost completely stop the keratinocytic synthesis of the lymphocyte-attracting chemokines CXCL9 and CXCL10. Furthermore, our ongoing work hints to an unexpected role of NFAT5, a member of the NFAT family, in the differentiation of keratinocytes and epidermal integrity. Among major putative NFAT5-controlled genes are kallikrein 7 (KLK7) and matrix metalloproteinase 3 (MMP3), which promote the differentiation of keratinocytes to corneocytes.Using mouse models of prototypical inflammatory skin diseases (lichenoid dermatitis, atopic eczema) we will investigate the role of NFAT factors in inflammatory processes and pathological keratinocyte differentiation by applying conditional NFATc1 and NFAT5 knockout mice. On the one hand, we want to understand the importance of NFAT factors for the first activation steps of (auto-)antigen-specific lymphocytes in the draining lymph nodes and for T lymphocyte invasion into the skin. On the other hand, we intend to investigate their direct and indirect influence on keratinocyte differentiation under steady-state and inflammatory conditions. The work program includes the use of molecular, cell biological and immunological methods to identify relevant T lymphocyte subpopulations in genetically modified mice and to genome-wide characterize NFAT-regulated gene expression programs in lymphocytes and the epidermis. Findings will be evaluated in parallel by analysis of lesional and non-lasional human skin and circulating lymphocytes from patients with lichen planus and atopic eczema as well as control individuals.Our proposed project will shed more light on the molecular mechanisms controlling human inflammatory skin diseases to specifically tackle NFAT-dependent signaling pathways for novel therapeutic approaches.