Show simple item record

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

dc.contributor.author Ingram, JT
dc.contributor.author Yi, John S
dc.contributor.author Zajac, AJ
dc.coverage.spatial United States
dc.date.accessioned 2015-06-16T18:54:53Z
dc.date.issued 2011-09
dc.identifier http://www.ncbi.nlm.nih.gov/pubmed/21980291
dc.identifier PPATHOGENS-D-11-01084
dc.identifier.uri https://hdl.handle.net/10161/10220
dc.description.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.
dc.language eng
dc.relation.ispartof PLoS Pathog
dc.relation.isversionof 10.1371/journal.ppat.1002273
dc.subject Animals
dc.subject CD8-Positive T-Lymphocytes
dc.subject Cytokines
dc.subject Down-Regulation
dc.subject Inflammation Mediators
dc.subject Interleukin-18 Receptor alpha Subunit
dc.subject Interleukin-2 Receptor alpha Subunit
dc.subject Listeria monocytogenes
dc.subject Listeriosis
dc.subject Mice
dc.subject Mice, Knockout
dc.title Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections.
dc.type Journal article
pubs.author-url http://www.ncbi.nlm.nih.gov/pubmed/21980291
pubs.begin-page e1002273
pubs.issue 9
pubs.organisational-group Clinical Science Departments
pubs.organisational-group Duke
pubs.organisational-group Duke Cancer Institute
pubs.organisational-group Institutes and Centers
pubs.organisational-group School of Medicine
pubs.organisational-group Surgery
pubs.organisational-group Surgery, Surgical Sciences
pubs.publication-status Published
pubs.volume 7
dc.identifier.eissn 1553-7374


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record