The role of IPS-1 and TRIF signaling in the in vivo dendritic cells differentiation and CD4+ t cell polarization during acute and chronic viral infection

Abstract

The development of the distinct subsets of dendritic cells (DCs) from monocytes and bone marrow precursors during homeostasis is mediated by the different transcription factors expressed and the cytokines present in the microenvironment. A number of these cytokines and their receptors is up-regulated upon infection, which can influence the expansion and the differentiation of the preformed DCs subsets. Stimulation and activation of DC upon viral infection is mainly given by the toll-like receptors (TLRs) and the RIG-I like receptors (RLRs) that, through signaling by distinct adaptors, lead to production of IFN-I and inflammatory cytokines. The signaling by these distinct adaptor molecules certainly induces distinct genetic programs in DCs, which may influence the priming and polarization of T lymphocytes. We initiated a study supported by FAPESP (n° 2012/20786-6) aimed to investigate the role of the signaling by the distinct adaptor molecules, IPS-1, TRIF and MyD88 in the differentiation of DCs in the distinct subsets and in the subsequent priming and polarization of T lymphocytes. Furthermore, we will associate the changes induced in differentiation of DCs and T cells with the outcome of acute and chronic viral infection. The expertise of Dr. Marco Colonna of Washington University in Saint Louis in dendritic cells and in acute and chronic viral infection models, as well as the IPS-1-/- and TRIF-/- mice that his laboratory has generated, will make us able to answer great part of these questions. In his labaratory, we aim to investigate the role of IPS-1 and TRIF in the in vivo DCs activation and CD4+ T cells polarization after viral infection. Furthermore, the bone marrow from IPS-1-/- and TRIF-/- mice will be frozen and taken back to FMRP in order to perform the in vitro differentiation of DCs necessary to the experiments proposed in the ongoing FAPESP project. (AU)