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

PLoS Negl Trop Dis. 2021 Jun 1;15(6):e0009473. doi: 10.1371/journal.pntd.0009473. eCollection 2021 Jun.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • CD8-Positive T-Lymphocytes / immunology
  • Chagas Disease / genetics
  • Chagas Disease / immunology*
  • Chagas Disease / parasitology
  • Chronic Disease
  • Female
  • Humans
  • Interleukin-27 / genetics
  • Interleukin-27 / immunology*
  • Interleukin-7 / genetics
  • Interleukin-7 / immunology
  • Leukocytes, Mononuclear / immunology
  • Male
  • Middle Aged
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology
  • Trypanosoma cruzi / genetics
  • Trypanosoma cruzi / physiology

Substances

  • IL27RA protein, human
  • Interleukin-27
  • Interleukin-7
  • Receptors, Interleukin
  • STAT3 Transcription Factor