RESUMO
Zika is an important emerging infectious disease in which the role of T cells remains elusive. This study aimed to evaluate the phenotype of multifunctional T cells in individuals 2 yr after exposure to Zika virus (ZIKV). We used a library of 671 synthetic peptides covering the whole polyprotein of ZIKV in pools corresponding to each viral protein (i.e., capsid, membrane precursor or prM, envelope, NS1 [nonstructural protein], NS2A + NS2B, NS3, NS4A + NS4B, and NS5) to stimulate PBMCs from individuals previously exposed to ZIKV. We observed an increased frequency of ZIKV-specific IFNγ, IL-17A, TNF, and IL-10 production by T cell populations. IFNγ and TNF production were especially stimulated by prM, capsid, or NS1 in CD8+ T cells and by capsid or prM in CD4+ T cells. In addition, there was an increase in the frequency of IL-10+ CD8+ T cells after stimulation with prM, capsid, NS1, NS3, or NS5. Multifunctional properties were observed in ZIKV-specific T cells responding especially to prM, capsid, NS1 or, to a smaller extent, NS3 antigens. For example, we found a consistent IFNγ + TNF+ CD8+ T cell population in response to most virus antigens and CD4+ and CD8+ T cells that were IFNγ + IL-17A+ and IL-17A+IL-10+, which could also produce TNF, in response to capsid, prM, NS1, or NS3 stimulation. Interestingly, CD8+ T cells were more prone to a multifunctional phenotype than CD4+ T cells, and multifunctional T cells were more efficient at producing cytokines than single-function cells. This work provides relevant insights into the quality of ZIKV-specific T cell responses and ZIKV immunity.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade Celular , Infecção por Zika virus/imunologia , Zika virus/imunologia , Adolescente , Adulto , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/patologia , Convalescença , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Virais/imunologia , Infecção por Zika virus/patologiaRESUMO
Multifunctional interleukin 10 (IL10)+ Th1 cells have been implicated in favorable evolution of many infectious diseases, promoting an efficacious immune response while limiting immunopathology. Here, we investigated the presence of multifunctional CD4+ and CD8+ T-cells that expressed interferon gamma (IFNγ), IL10 and tumor necrosis factor (TNF), or its combinations during dengue infection. Peripheral blood mononuclear cells (PBMCs) from outpatients with dengue (mild dengue forms) and hospitalized patients (or patients with dengue with warning signs and severe dengue) were cultured in the presence of envelope (ENV) or NS3 peptide libraries of DENV during critical (hospitalization period) and convalescence phases. The production of IFNγ, IL10 and TNF by CD4+ and CD8+ T-cells was assessed by flow cytometry. Our data show that patients with mild dengue, when compared with patients with dengue with warning signs and severe dengue, presented higher frequencies of multifunctional T-cells like NS3-specific IFNγ/IL10-producing CD4+ T-cells in critical phase and NS3- and ENV-specific CD8+ T-cells producing IFNγ/IL10. In addition, NS3-specific CD8+ T-cells producing high levels of IFNγ/TNF and IFNγ/TNF/IL10 were also observed in the mild dengue group. We observed that multifunctional T-cells produced higher levels of cytokines as measured by intracellular content when compared with single producer T-cells. Importantly, multifunctional CD4+ and CD8+ T-cells producing IFNγ, TNF and IL10 simultaneously displayed positive correlation with platelet levels, suggesting a protective role of this population. The presence of IL10+ Th1 and IL10+ Tc1 multifunctional cells was associated with mild dengue presentation, suggesting that these cells play a role in clinical evolution of dengue infection.
Assuntos
Dengue/diagnóstico , Dengue/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Antígenos Virais/imunologia , Brasil , Estudos de Casos e Controles , Dengue/sangue , Vírus da Dengue/imunologia , Feminino , Voluntários Saudáveis , Humanos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , RNA Helicases/imunologia , Serina Endopeptidases/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas não Estruturais Virais/imunologia , Adulto JovemRESUMO
Excess intake of sodium is often associated with high risk for cardiovascular disease. More recently, some studies on the effects of high-salt diets (HSDs) have also demonstrated that they are able to activate Th17 cells and increase severity of autoimmune diseases. The purpose of the present study was to evaluate the effects of a diet supplemented with NaCl in the colonic mucosa at steady state and during inflammation. We showed that consumption of HSD by mice triggered a gut inflammatory reaction associated with IL-23 production, recruitment of neutrophils, and increased frequency of the IL-17-producing type 3 innate lymphoid cells (ILC3) in the colon. Moreover, gut inflammation was not observed in IL-17-/- mice but it was present, although at lower grade, in RAG-/- mice suggesting that the inflammatory effects of HSD was dependent on IL-17 but only partially on Th17 cells. Expression of SGK1, a kinase involved in sodium homeostasis, increased 90 min after ingestion of 50% NaCl solution and decreased 3 weeks after HSD consumption. Colitis induced by oral administration of either dextran sodium sulfate or 2,4,6-trinitrobenzenesulfonic acid was exacerbated by HSD consumption and this effect was associated with increased frequencies of RORγt+ CD4+ T cells and neutrophils in the colon. Therefore, our results demonstrated that consumption of HSD per se triggered a histologically detectable inflammation in the colon and also exacerbated chemically induced models of colitis in mice by a mechanism dependent on IL-17 production most likely by both ILC3 and Th17 cells.