IL-18BP mediates the balance between protective and pathological immune responses to Toxoplasma gondii.

Abstract

Interleukin-18 (IL-18) promotes natural killer (NK) and T cell production of interferon (IFN)-γ, a key factor in resistance to Toxoplasma gondii, but previous work has shown a limited role for endogenous IL-18 in control of this parasite. Although infection with T. gondii results in release of IL-18, the production of IFN-γ induces high levels of the IL-18 binding protein (IL-18BP). Antagonism of IL-18BP with a "decoy-to-the-decoy" (D2D) IL-18 construct that does not signal but rather binds IL-18BP results in enhanced innate lymphoid cell (ILC) and T cell responses and improved parasite control. In addition, the use of IL-18 resistant to IL-18BP ("decoy-resistant" IL-18 [DR-18]) is more effective than exogenous IL-18 at promoting innate resistance to infection. DR-18 enhances CD4+ T cell production of IFN-γ but results in CD4+ T cell-mediated pathology. Thus, endogenous IL-18BP restrains aberrant immune pathology, and this study highlights strategies that can be used to tune this regulatory pathway for optimal anti-pathogen responses.

• Authors: Joseph T Clark, Orr-El Weizman, Daniel L Aldridge, Lindsey A Shallberg, Julia Eberhard, Zachary Lanzar, Devon Wasche, John D Huck, Ting Zhou, Aaron M Ring, Christopher A Hunter
• Journal: Cell reports (Cell Rep) Vol. 42 Issue 3 Pg. 112147 (03 28 2023) ISSN: 2211-1247 [Electronic] United States
• PMID: 36827187 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-18
• interleukin-18 binding protein
• Interleukin-12

Topics

• Humans
• Animals
• Toxoplasma
• Interleukin-18 (metabolism)
• Killer Cells, Natural
• Interleukin-12 (metabolism)
• Immunity, Innate
• Toxoplasmosis, Animal