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.
Type
Journal articleSubject
AnimalsCD8-Positive T-Lymphocytes
Cytokines
Down-Regulation
Inflammation Mediators
Interleukin-18 Receptor alpha Subunit
Interleukin-2 Receptor alpha Subunit
Listeria monocytogenes
Listeriosis
Mice
Mice, Knockout
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https://hdl.handle.net/10161/10220Published Version (Please cite this version)
10.1371/journal.ppat.1002273Publication Info
Ingram, Jennifer T; Yi, John S; & Zajac, Allan J (2011). Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory
cytokines and bacterial co-infections. PLoS Pathog, 7(9). pp. e1002273. 10.1371/journal.ppat.1002273. Retrieved from https://hdl.handle.net/10161/10220.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
John S Yi
Adjunct Assistant Professor in the Department of Surgery
I am an immunologist, with a focus to characterize the immune system in response to
infectious and non-infectious diseases including cancer, HIV, autoimmune disease,
and transplantation. My goals are to identify novel biomarkers/immune signatures that
clinicians can utilize to diagnosis, predict disease outcomes, and determine patients'
response to treatment.

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