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Modulation of the immune response by plasmacytoid and myeloid dendritic cells against the fungus Paracoccidioides brasiliensis: involvement of immunosuppressive mechanisms dependent on IL-27 cytokine

Grant number: 17/11391-1
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): September 01, 2017
Effective date (End): August 31, 2018
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Vera Lucia Garcia Calich
Grantee:Bruno Borges da Silva
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Dendritic cells (DCs) are the main link between innate and adaptive immunities. Depending on the subclass and activation pattern, they play an important role in regulating immunological process that could be protective and deleterious to the hosts. The role of DCs in paracoccidioidomycosis (PCM), the most prevalent deep mycosis in Latin America, has been little studied, although several studies have characterized the main parameters of the adaptive immune response in the mild and severe forms of the disease. In previous work it was demonstrated that the resistance and susceptibility to Paracoccidioides brasiliensis were associated to different subpopulations and functions of DCs. Our results demonstrated that the pDCs present a tolerogenic profile by mechanisms regulated by the production of immunosuppressive cytokines such as IL-27 and IL-35, as well as the expansion of regulatory T cells (Treg), which promoted impaired Th1/Th17 protective responses. These data justify new studies about the function of human DCs (myeloids and plasmacytoids) in PCM, as well as better explain the function of the IL-27 cytokine as modulators of the immune response against the fungus. For this, we intend to evaluate the production of IL-27 cytokine in DCs infected with P. brasiliensis yeasts. In addition, we will inhibit DCs with anti-IL-27 antibodies, or treat with recombinant IL-27 protein in order to study the immunomodulatory profile of these cells in co-culture with lymphocytes in the presence and absence of IL-27. Lymphocytes will be evaluated for their activation and patterns of Th1, Th2, Th17, Treg (Tr1 and FoxP3) immune responses. (AU)