Abstract
Little is known about the role of chemokines/chemokines receptors on T cells in natural DENV infection. Patients from DENV-2 and -3- outbreaks were studied prospectively during the acute or convalescent phases. Expression of chemokine receptor and activation markers on lymphocyte subpopulations were determined by flow cytometry analysis, plasma chemokine ligands concentrations were measured by ELISA and quantification of CCL5/RANTES+ cells in liver tissues from fatal dengue cases was performed by immunochemistry. In the acute DENV-infection, T-helper/T-cytotoxic type-1 cell (Th1/Tc1)-related CCR5 is significantly higher expressed on both CD4 and CD8 T cells. The Th1-related CXCR3 is up-regulated among CD4 T cells and Tc2-related CCR4 is up-regulated among CD8 T cells. In the convalescent phase, all chemokine receptor or chemokine ligand expression tends to reestablish control healthy levels. Increased CCL2/MCP-1 and CCL4/MIP-1β but decreased CCL5/RANTES levels were observed in DENV-patients during acute infection. Moreover, we showed an increased CD107a expression on CCR5 or CXCR3-expressing T cells and higher expression of CD29, CD44HIGH and CD127LOW markers on CCR4-expressing CD8 T cells in DENV-patients when compared to controls. Finally, liver from dengue fatal patients showed increased number of cells expressing CCL5/RANTES in three out of four cases compared to three death from a non-dengue patient. In conclusion, both Th1-related CCR5 and CXCR3 among CD4 T cells have a potential ability to exert cytotoxicity function. Moreover, Tc1-related CCR5 and Tc2-related CCR4 among CD8 T cells have a potential ability to exert effector function and migration based on cell markers evaluated. The CCR5 expression would be promoting an enhanced T cell recruitment into liver, a hypothesis that is corroborated by the CCL5/RANTES increase detected in hepatic tissue from dengue fatal cases. The balance between protective and pathogenic immune response mediated by chemokines during dengue fever will be discussed.
Highlights
Dengue fever (DF) is usually a self-limiting yet debilitating febrile illness, but occasionally it may present severe clinical manifestations that are life-threatening and are characterized by increased vascular permeability, thrombocytopenia, hemorrhages and shock [1]
We investigated here the expression of inflammatory chemokine receptors CCR5, CXCR3, and CCR4 in circulating T cells and the CCR5 ligands during dengue infection, since those receptors play a crucial role in governing the immune response against most diverse viruses
We showed that during acute course of Dengue virus (DENV)-infection, a Th1/Tc1 profile occurs that is characterized by CCR5 expression on both CD4 and CD8 T cell populations
Summary
Dengue fever (DF) is usually a self-limiting yet debilitating febrile illness, but occasionally it may present severe clinical manifestations that are life-threatening and are characterized by increased vascular permeability, thrombocytopenia, hemorrhages and shock [1]. Severe DF is most often observed in individuals experiencing a secondary infection with a heterologous serotype [2], and it has been postulated that serotype cross-reactive antibodies and memory T cells are involved in the pathogenesis [3,4]. Serotype-cross-reactive T cells are preferentially activated during a second DENV infection in a phenomenon termed as ‘‘original antigenic sin’’, indicating a pathogenic role of T cells during sequential DENV infections [5]. These cross-reactive T cells have exhibit suboptimal degranulation and altered cytokine production [6,7,8]. The role of T cells in protection versus pathogenesis during DENV infections still presents some unclear aspects
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