title: 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: Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors: Jennifer T
authors: JT
authors: Ingram
authors: John S
authors: JS
authors: Yi
authors: Allan J
authors: AJ
authors: Zajac
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D053727:Interleukin-18 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout
chemical_list: D016207:Cytokines; C508573:Il18r1 protein, mouse; C508018:Il2ra protein, mouse; D018836:Inflammation Mediators; D053727:Interleukin-18 Receptor alpha Subunit; D053645:Interleukin-2 Receptor alpha Subunit