RESUMO
Chagas disease, caused by the intracellular pathogen Trypanosoma cruzi, is the parasitic disease with the greatest impact in Latin America and the most common cause of infectious myocarditis in the world. The immune system plays a central role in the control of T. cruzi infection but at the same time needs to be controlled to prevent the development of pathology in the host. It has been shown that persistent infection with T. cruzi induces exhaustion of parasite-specific T cell responses in subjects with chronic Chagas disease. The continuous inflammatory reaction due to parasite persistence in the heart also leads to necrosis and fibrosis. The complement system is a key element of the innate immune system, but recent findings have also shown that the interaction between its components and immune cell receptors might modulate several functions of the adaptive immune system. Moreover, the findings that most of immune cells can produce complement proteins and express their receptors have led to the notion that the complement system also has non canonical functions in the T cell. During human infection by T. cruzi, complement activation might play a dual role in the acute and chronic phases of Chagas disease; it is initially crucial in controlling parasitemia and might later contributes to the development of symptomatic forms of Chagas disease due to its role in T-cell regulation. Herein, we will discuss the putative role of effector complement molecules on T-cell immune exhaustion during chronic human T. cruzi infection.
Assuntos
Doença de Chagas , Miocardite , Trypanosoma cruzi , Doença de Chagas/parasitologia , Proteínas do Sistema Complemento , Humanos , Linfócitos TRESUMO
In chronic Chagas disease, Trypanosoma cruzi-specific T-cell function decreases over time, and alterations in the homeostatic IL-7/IL-7R axis are evident, consistent with a process of immune exhaustion. IL-27 is an important immunoregulatory cytokine that shares T-cell signaling with IL-7 and other cytokines of the IL-12 family and might be involved in the transcriptional regulation of T-cell function. Here, we evaluated the expression and function of IL-27R in antigen-experienced T cells from subjects with chronic Chagas disease and assessed whether in vitro treatment with IL-27 and IL-7 might improve T. cruzi-specific polyfunctional T-cell responses. In vitro exposure of PBMCs to T. cruzi induced a downregulation of IL-27R in CD4+ T cells and an upregulation in CD8+ T cells in subjects without heart disease, while IL-27R expression remained unaltered in subjects with more severe clinical stages. The modulation of IL-27R was associated with functional signaling through STAT3 and STAT5 and induction of the downstream genes TBX21, EOMES and CXCL9 in response to IL-27. In vitro treatment of PBMCs with IL-27 and IL-7 improved monofunctional and polyfunctional Th1 responses, accompanied by the induction of IL-10 and Bcl-2 expression in subjects without heart disease but did not improve those in subjects with cardiomyopathy. Our findings support the process of desensitization of the IL-27/IL-27R pathway along with disease severity and that the pro-inflammatory and immunomodulatory mechanisms of IL-27 might be interconnected.