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

Abstract

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.

C57BL/6 Mice Pretreated With Alpha-Tocopherol Show a Better Outcome of Trypanosoma cruzi Infection With Less Tissue Inflammation and Fibrosis

“…Memory CD8 + T cells are crucial in infection control, especially in the infected tissues (38,39). However, it was also described that memory T cells might acquire a non-functional phenotype in peripheral tissues either in tumor environments or during T cruzi infection, the so-called exhausted or dysfunctional phenotype (40,41). Therefore, the simple presence of increased numbers of effector memory T cells does not guarantee a better immune response.…”

Intra-host Trypanosoma cruzi strain dynamics shape disease progression: the missing link in Chagas disease pathogenesis

“…A major issue is that disease progression is still poorly understood, and patients at an increased risk of developing severe disease cannot be distinguished from those who may remain in the asymptomatic chronic stage, making any prognosis uncertain. Pathogenesis has been associated with immune exhaustion, allowing parasite persistence in host tissues ( 3 , 4 ), providing the rationale to target the parasite through drugs or therapeutic vaccines ( 2 ). However, the efficacy of benznidazole treatment is variable, and while it can consistently decrease parasite burden, it can also delay the appearance of new electrocardiographic (ECG) abnormalities and the progression to more severe Kuschnir group of cardiac disease in patients treated early ( 5 , 6 ), but it fails to stop or delay the progression of fibrotic heart disease in symptomatic patients ( 7 ).…”