Trypanosoma cruzi-specific IFN-γ-producing cells in chronic Chagas disease associate with a functional IL-7/IL-7R axis

Abstract

BackgroundThe severity of cardiac disease in chronic Chagas disease patients is associated with different features of T-cell exhaustion. Here, we assessed whether the ability of T cells to secrete IFN-γ in response to T. cruzi was linked to disruption in immune homeostasis and inflammation in patients with chronic Chagas disease.Methodology/Principal findingsPBMCs from chronic Chagas disease patients and uninfected controls were examined for frequencies of T. cruzi-responsive IFN-γ-producing cells by ELISPOT and cellular expression and function of IL-7R using flow cytometry. Serum levels of IL-7, IL-21, IL-27, soluble IL-7R, and inflammatory cytokines were also evaluated by ELISA or CBA techniques. Patients possessing T. cruzi-specific IFN-γ-producing cells (i.e. IFN-γ producers) had higher levels of memory T cells capable of modulating the alpha chain of IL-7R and an efficient response to IL-7 compared to that in patients lacking (i.e. IFN-γ nonproducers) parasite-specific T-cell responses. IFN-γ producers also showed low levels of soluble IL-7R, high basal expression of Bcl-2 in T cells and low basal frequencies of activated CD25+ T cells. Modulation of IL-7R was inversely associated with serum IL-6 levels and positively associated with serum IL-8 levels. Circulating IL-21 and IL-27 levels were not associated with the frequency of IFN-γ producing cells but were reduced in less severe clinical forms of the disease. In vitro stimulation of PBMCs with IL-7 or IL-27 enhanced IFN-γ production in IFN-γ producers but not in IFN-γ nonproducers.Conclusions/SignificanceAlterations of the IL-7/IL-7R axis and in the levels of inflammatory cytokines were linked to impaired T. cruzi-specific IFN-γ production. These alterations might be responsible of the process of immune exhaustion observed in chronic Chagas disease.

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

“…cruzi infection of mice, the deficiency of IL-27 or WSX-1 inhibited the control of parasite burden despite the elevated production of inflammatory cytokines [ 30 – 32 ]. Whereas previous findings of our group have shown decreased IL-27 serum levels in patients with no signs of cardiac dysfunction [ 14 ], other authors have reported increased levels of IL27p28 in these patients [ 32 ]. However, it is unknown whether the signaling pathway of IL-27/IL-27R is functional in the chronic phase of Chagas disease in humans.…”

“…We have shown that the levels of IFN-γ-producing cells in response to T . cruzi antigens are positively associated with the expression and function of the receptor of homeostatic IL-7 in T cells and can be augmented after in vitro stimulation with IL-7 or IL-27 [ 14 ]. IL-27 can mediate the differentiation and proliferation of Th1 cells [ 15 ], activation of cytotoxic CD8 + T lymphocytes [ 16 ] and NK cells [ 17 ], and suppression of Th2 [ 18 ].…”

MiR-144-3p is associated with pathological inflammation in patients infected with Mycobacteroides abscessus

“…1e). In addition, IL-7, a crucial cytokine for T-helper 1 responses [23][24][25][26] , was the most downregulated gene, with an~6-fold decrease in both types of patients.…”

Interleukin (IL)-21 in Inflammation and Immunity During Parasitic Diseases

“…The serum levels of several cytokines, including IL-21, positively correlated with disease severity in patients with chronic Chagas disease caused by T. cruzi (Natale et al, 2018). Consistently, lower levels of IL-21 production were observed in the sera of human subjects with less severe cardiac dysfunction as compared with those presented with an advanced cardiac dysfunction profile (Natale et al, 2018). These observations may suggest a potential role for the IL-21/IL-21R axis in the promotion of pathology in chronically-infected human subjects.…”