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Evaluation of the capability of differentiation of Th17 cells by dendritic cells stimulated with Paracoccidioides brasiliensis yeast cells and intracellular signaling mechanisms involved

Maria Carolina Ferreira
Total Authors: 1
Document type: Doctoral Thesis
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
Defense date:
Examining board members:
Jacy Gameiro; Luciane Alarcão Dias Melício; Leonilda Maria Barbosa dos Santos; Plínio Trabasso
Advisor: Ronei Luciano Mamoni

Paracoccidioidomycosis (PCM), caused by the dimorphic fungus Paracoccidioides brasiliensis (Pb), is the most prevalent systemic mycosis in Brazil. Previous studies showed that resistance or susceptibility to PCM can be associated to a Th1 or Th2 responses respectively. More recently, Th17 response was showed to be protective in fungal infections, but there is no data about Th17 cells in human PCM. T CD4+ differentiation is elicited and shaped after pathogen recognition by dendritic cells (DCs) through several PRRs, which modulate Th1, Th2 and Th17 generation. In this study we evaluated the role of TLR-2, TLR-4 and Dectin-1 in the recognition of Pb yeast cells by monocytes derived DCs, as well as, the capability of these DCs to modulate T CD4+ lymphocytes differentiation. We observed that DCs exposed to Pb presented a mature phenotype (expression of CCR7, CD83, CD80, CD86 and MHC II) and produce cytokines (IL-1, IL-6, IL-23, TNF-α and TGF- ) that promote the differentiation of TCD4+ lymphocytes producing IL- 7, IFN-γ, IL-22, IL-17/IL-22 and IL-17/IFN-γ. We also observed that DCs stimulated by Pb presented activation of molecules involved in the TLRs and dectin-1 signaling (JNK, p38, AKT, ERK - for TLRs and Syk for dectin- The blockage of dectin-1 and/or TLR2 diminished the differentiation of Th17 cells. We also analyzed PBMCs from patients with the acute/juvenile form (JF) or the chronic/adult form (AF) of PCM. Our results showed that patients with JF present elevated production of IL-4 and AF patients present higher production of IL-17. Altogether our results showed that Dectin-1 and TLR-2 are the most important receptors for human DCs to recognize Pb yeast cells and to produce cytokines such as IL- , IL- β and TNF-α. After DC activation and cytokine production these cells are able to induce Th1 and Th17 differentiation through these receptors. Also we showed that Th17 cells are a major population in AF patients. (AU)

FAPESP's process: 09/05608-1 - Evaluation of the ability of diferentiation induction of Th7 cells by dendritic cells stimulated with Paracoccidoides brasiliensis antigens and the signaling mechanisms envolved.
Grantee:Maria Carolina Ferreira
Support type: Scholarships in Brazil - Doctorate