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Molecular mechanisms involved in dendritic cell differentiation and CD4+ T cells polarization that confer resistance to viral infection

Grant number: 12/20786-6
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): January 01, 2014
Effective date (End): November 30, 2016
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:João Santana da Silva
Grantee:Renata Sesti Costa
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:12/14524-9 - Modulation of T lymphocytes differentiation in infections by Protozoa, Fungi and Bacteria, AP.TEM
Associated scholarship(s):14/04044-5 - 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, BE.EP.PD


Dendritic cells (DC) are a heterogeneous group of cells divided in several subsets that, although share the common function of antigen presentation, they play distinct roles in immune response. Although it has been well studied the different cytokines and transcription factors that induce the development of the distinct subsets of DCs from monocytes and bone marrow precursors during homeostasis, a number of these cytokines and their receptors is upregulated upon inflammation, which can influence the expansion and the differentiation of the preformed DCs subsets after an inflammatory stimulus. Furthermore, cDC precursors are able to differentiate into distinct subsets late during infection. So, a major challenge now is determine the changes induced by inflammatory stimuli that ensure the differentiation in specific DC subsets and their subsequent contribution to immune response and maintenance of tolerance. 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. RLRs are cytoplasmic receptors that recognize viral RNAs and signal through the adaptor IPS-1, whereas the TLRs that recognize RNA comprised the endossomal TLR3 and TLR7/8, which signal through the adaptor molecules TRIF and MyD88, respectively. The signaling by these distinct adaptor molecules certainly induces distinct genetic programs in DCs, which may influence the priming and differentiation of CD4+ T lymphocytes during immunological sinapse to the diverse known subtypes, as Th1, Th2, Th17, Th9, Th22 and regulatory T cells. Thus, this study aim to understand the role of the DC activation by distinct adaptor molecules in the differentiation in distinct DC subsets and in the subsequent priming and differentiation of CD4+ T lymphocytes in the diverse cell subtypes. Furthermore, we will associate the changes induced in differentiation of DCs and CD4+ T cells with the outcome of acute and chronic viral infection. The findings of this study may help to elucidate the mechanisms by which distinct stimuli induce different responses of CDs during the polarization of adaptive immune response. Furthermore, they may lead to new insights in the development of new effective adjuvants in vaccines for viral infections.

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SESTI-COSTA, RENATA; SANTIAGO FRANCOZO, MARCELA CRISTINA; SILVA, GRACE KELLY; PROENCA-MODENA, JOSE LUIZ; SILVA, JOAO SANTANA. TLR3 is required for survival following Coxsackievirus B3 infection by driving T lymphocyte activation and polarization: The role of dendritic cells. PLoS One, v. 12, n. 10, . (13/08216-2, 12/20786-6)

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