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| Author(s): |
Larissa Nara Alegrini Longhi
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2014-07-28 |
| Examining board members: |
Ronei Luciano Mamoni;
Angela Maria Victoriano de Campos Soares;
Luciane Alarcão Dias Melício;
Plinio Trabasso;
Liana Maria Cardoso Verinaud
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| Advisor: | Maria Heloisa de Souza Lima Blotta; Ronei Luciano Mamoni |
| Abstract | |
Several studies have shown that the innate immune response presents a fundamental role in controlling the adaptive immune response. In a previous study we demonstrated that natural killer cells (NK) participate in the immune response to Paracoccidioides brasiliensis, the etiological agent of paracoccidioidomycosis (PCM). Currently it is known that dendritic cells (DCs) are able to interact with NK cells, increasing its activity. The objective of this study was to evaluate the mechanism used by NK cells in the recognition of P. brasiliensis yeast cells and, whether DCs stimulated by the fungus are able to interact with NK cells and therefore influence the differentiation of T lymphocytes. We used DCs derived from monocytes and CD56 + (NK) cells isolated from peripheral blood of healthy individuals. We analyzed the role of some toll-like receptors (TLR-2 and TLR-4) and the complement receptor 3 (CR3 - CD11b) in the recognition of P. brasiliensis NK cells. Our results showed that the CR3 is probably more important, since that its blockage decreased the activation and the direct cytotoxic activity of NK cells against the fungus. Furthermore, activation via TLR2, together with CR3, leads to the production of cytokines such as IFN-gamma and TNF-alpha. Moreover, our results demonstrated that DCs stimulated with the fungus are activated and produce cytokines important for the activation of NK cells (IL-12, IL-18, IL-23 and IL-15). NK cells stimulated with these cytokines or co-cultured with DCs (previously stimulated with yeast cells) presented greater capacity for proliferation, increased expression of activation markers (CD25 and CD69), increased fungicide capacity and increased production of cytokines such as IFN-gamma and TNF-alpha. These effects were partially dependent on contact, probably involving the participation of membrane associated IL-15, and also the production of soluble cytokines (IL-12, IL-23 and IL-18) by DCs. In addition, the interaction between NK cells and DCs leads to an increased expression of molecules important for the antigen presentation to T cells, such as costimulatory molecules (CD80 and CD86) and class II MHC on DCs. We also observed that the interaction between DCs (stimulated with the fungus) and NK cells increased the differentiation of T CD4+ and T CD8+ cells into IFN-gamma producing lymphocytes, while inhibited the differentiation of IL-4 producing T lymphocytes. Altogether our results demonstrate that the crosstalk between DCs and NK cells stimulated with P. brasiliensis yeast cells leads to an increased activation of both DCs and NK cells, and that this interaction can be important for modulating the subsequent acquired immune response against the fungus (AU) | |
| FAPESP's process: | 11/07481-9 - Evaluation of the interaction between NK cells and Dendritic Cells in the immunological response against Paracoccidioides brasiliensis |
| Grantee: | Larissa Nara Alegrini Longhi |
| Support Opportunities: | Scholarships in Brazil - Doctorate |