Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections.

Abstract

During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon (IFN)-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. The unresponsiveness of exhausted CD8 T cells is associated with downregulation of the IL-18-receptor-α (IL-18Rα). Although IL-18Rα expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Rα(lo) exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Rα downregulation, we tracked the fate of IL-18Rα-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Rα affects the initial but not later phases of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18Rα(hi) memory cells upregulated CD25 and produced IFN-γ, the IL-18Rα(lo) exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections.

• Authors: Jennifer T Ingram, John S Yi, Allan J Zajac
• Journal: PLoS pathogens (PLoS Pathog) Vol. 7 Issue 9 Pg. e1002273 (Sep 2011) ISSN: 1553-7374 [Electronic] United States
• PMID: 21980291 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Il18r1 protein, mouse
• Il2ra protein, mouse
• Inflammation Mediators
• Interleukin-18 Receptor alpha Subunit
• Interleukin-2 Receptor alpha Subunit

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cytokines (biosynthesis, genetics, immunology)
• Down-Regulation (genetics, immunology)
• Inflammation Mediators (immunology, metabolism)
• Interleukin-18 Receptor alpha Subunit (biosynthesis, genetics, immunology)
• Interleukin-2 Receptor alpha Subunit (genetics, immunology, metabolism)
• Listeria monocytogenes (immunology)
• Listeriosis (genetics, immunology, metabolism)
• Mice
• Mice, Knockout