Demonstration of calcineurin-dependent NFAT activation in DC via CD14 but not TLR4
Our group obtained data on molecular signaling triggered by LPS in dendritic cells and the role of CD14 in the regulation of the DC life cycle through NFAT activation. Toll-like receptors (TLRs) are the best-characterized pattern recognition receptors (PRRs). Individual TLRs recruit diverse combinations of adapter proteins, and thereby trigger signal transduction pathways leading to the activation of various transcription factors, including nuclear factor (NF)-kB, activation protein (AP)-1, and interferon regulatory factors (IRFs). Interleukin-2 (IL-2) is one of the molecules produced by mouse dendritic cells (DCs) after stimulation by TLR agonists. By analogy with the events following T-cell receptor (TCR) engagement leading to IL-2 production, it is therefore plausible that the stimulation of TLRs on DCs may lead to activation of the Ca2+/calcineurin and NFAT pathway. Our contribution to the project has been the finding that the DC stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase C (PLC)?2 activation, influx of extracellular Ca2+ and calcineurin-dependent nuclear NFAT translocation. The initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. We also show that LPS-induced NFAT activation via CD14 is necessary to cause death of terminally differentiated DCs (supplementary Fig. 1), an event that is essential for maintaining self-tolerance and preventing autoimmunity. Consequently, blocking this pathway in vivo causes prolonged DC survival and an increase in T cell priming capability. Our findings reveal novel aspects of the molecular signaling triggered by LPS in DCs and identify a new role for CD14: the regulation of the DC life cycle through NFAT activation.
Role of Toll like receptor-activated dendritic cells in the development of autoimmunity
Central role of dendritic cells in the regulation and deregulation of immune responses.