Study of the role of NFAT pathway in the innate immune system

DCs sense and respond to a wide range of microorganism through specialized germline-encoded receptors called PRRs, which are able to recognize molecular patterns expressed by various microorganisms and endogenous stimuli. Following activation with LPS, DCs sequentially acquire the ability to produce soluble and cell surface molecules critical for the initiation and control of innate and then adaptive immune responses. The production of most of these factors is regulated by the activation of TLR4-MD2 pathway. Nevertheless, in my laboratory it has been recently demonstrated that, following LPS exposure, different NFAT isoforms are also activated [63]. The initiation of the pathway that leads to nuclear NFAT translocation is totally dependent on CD14 that, through the activation of src family kinases and PLCγ2, leads to Ca2+ mobilization and calcineurin activation. Nuclear NFAT translocation is required for IL-2 production and apoptotic cell death of terminally differentiated DCs. In the present work, we analyzed the role of CD14-NFAT pathway in a preclinical model of skin edema formation and its implications in antigen delivery. In addition we propose a new NFAT inhibitor as tool for studying in vivo the role of the activation of CD14-NFAT pathway in DCs in a model of acute transplant rejection.