Leishmania amazonensis prejudica resposta de células dendríticas via inibição da expressão de CD40 mediada por ectonucleotidases e pela ativação do receptor de adenosina A2B / Leishmania amazonensis prejudica resposta de células dendríticas via inibição da expressão de CD40 mediada por ectonucleotidases e pela ativação do receptor de adenosina A2B

Amanda Braga de Figueiredo

Leishmania infections can result in a wide spectrum of clinical manifestations, and the outcome of disease is determined by parasite species and the host immune response. Dendritic cells play an essential role in the modulation of immune response including during Leishmania infection. Extracellular-ATP exhibits pro-inflammatory properties whereas adenosine is an important anti-inflammatory mediator. Based on these assumptions, our objective was to investigate the effects of Leishmania infection on dendritic cells response and the participation of purinergic signaling in this process. C57BL/6J bone marrow dendritic cells were infected with CFSE-labeled metacyclic promastigotes of L. amazonensis, L. braziliensis or L. major (1:3 cell to parasite ratio). Infected cells decreased the expression of MHCII and CD86, independent of the parasite specie. The expression of CD40 was significantly increased in dendritic cells infected with L. braziliensis or L. major, when compared with uninfected dendritic cells. On the other hand, CD40 expression was not changed in L. amazonensis infected dendritic cells, and these cells presented a reduced ability to induce T cell proliferation, in mixed leukocyte reaction and antigen-specific proliferation assays. To describe the mechanisms involved in this process, we initially analyzed the production of IL-10 in culture supernatants by ELISA and found no differences between control and infected dendritic cells cultures. Blockade of IL-10 receptor by 1B1.3a antibody partially restored the MHCII and CD86 expression in L. braziliensis or L. major infected dendritic cells, but not in L. amazonensis infected dendritic cells. Co-expression of ectonucleotidases CD39 and CD73 and enzymatic activity of these enzymes were significantly increased in infected cells and the inhibition of extracellular ATP hydrolysis by suramin increased the expression of MHCII and CD86, regardless of parasite specie used. Interestingly, the presence of MRS1754, a highly selective A2B adenosine receptor antagonist, at the time of infection, increased the expression of MHCII and CD86 and CD40 only in L. amazonensis infected dendritic cells, cells with differentiated expression of this receptor, and recovered dendritic cells ability to induce T cell proliferation. In conclusion, different species of Leishmania use different mechanisms to evade the immune response, and we propose that ectonucleotidases activity and activation of A2B receptor of dendritic cells may be used by L. amazonensis to this aim.

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