Immune exhaustion in chronic Chagas disease: Pro-inflammatory and immunomodulatory action of IL-27 in vitro

Author summary Chagas disease, caused by the intracellular protozoan parasite Trypanosoma cruzi, affects approximately 10 million people worldwide. In 20%-30% of infected individuals, the disease results in heart disease or mega esophagus/megacolon, making Chagas disease the most common cause of infectious myocarditis in the world. Previous studies have shown that the immune response specific for this parasite becomes impaired over time. One mechanism that could explain the loss of immune cells is the defective signaling of cytokines involved in the maintenance of T cells. In this work, we evaluated the signaling pathways of IL-27 and IL-7, which promote T-cell differentiation, but IL-27 might also exert immunomodulatory actions. We found alterations in the IL-27/IL-7 pathways in chronic Chagas disease that affect not only the signal-transduction level but also the transcriptional regulation level. In vitro treatment of PBMCs of patients in early clinical stages of chronic Chagas disease could restore T-cell function, but this was not possible in cell cultures from patients with severe heart disease in whom the immune system is deeply exhausted. These findings contribute to a better understanding of the immune mechanisms underlying the anti-T. cruzi response in human subjects which might be useful for vaccine and new therapeutic interventions. 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.