Mecanismos de regulação da resposta imune na dengue humana

Abstract

Introduction: Dengue is a viral infection and can be classified into mild dengue, usually treated at home, and dengue with warning signs (sa+) and severe dengue (sa+/severe), which require hospitalization. Severe manifestations of dengue are considered to be the result of exacerbated activation of the immune response. The importance of regulatory mechanisms promoted by anti-inflammatory molecules and cytokines of multifunctional and regulatory T cells (Tregs) in controlling inflammatory responses is evident in many infectious diseases. Therefore, our objective was to investigate the presence of these mechanisms in different clinical forms of dengue infection. Methods and Results: Peripheral blood mononuclear cells (PBMCs) from dengue patients were cultured in the presence of the peptide library for the viral envelope proteins (ENV) or NS3 of DENV1. Patients with mild dengue had higher plasma levels of IFNγ, TNF and IL12p70 when compared to the sa+/severe group. The frequencies of specific CD4+ or CD8+ T cells producing single or double DENV (TNF or IL10 or IFNγ/TNF or IFNγ/IL10) were higher in mild dengue when compared to sa+/severe clinical forms. Furthermore, patients with mild dengue had higher levels of triple NS3-specific T cells producing IFNγ, TNF, and IL10 than the sa+/severe group. Among the regulatory molecules evaluated, we verified that patients with dengue increase the frequencies of Teff GITR+ or LAP+ or PD1+ cells, and Tregs CD226+ and CTLA4+ cells. On the other hand, patients with mild dengue showed high frequencies of CD200+ Tregs and, importantly, high frequencies of GITR+ tTregs that produce IL10 specific to DENV, a population that is rarely used in patients with sa+/severe dengue. Furthermore, using epitope mapping of the DENV1 ENV peptide library, we were able to identify peptides associated with IL10 production by Tregs. Conclusion: The clinical evolution of dengue seems to be related to regulatory mechanisms of the immune response. Tregs from individuals with sa+/severe dengue showed an important deficiency in activation markers, suggesting a dysfunctional phenotype, and the production of IL10 by multifunctional T cells and by tTregs GITR+ cells is associated with the clinical presentation of mild dengue, suggesting that these regulatory mechanisms are important to limit dengue immunopathology.