| First Author | Ingram JT | Year | 2011 |
| Journal | PLoS Pathog | Volume | 7 |
| Issue | 9 | Pages | e1002273 |
| PubMed ID | 21980291 | Mgi Jnum | J:183336 |
| Mgi Id | MGI:5318430 | Doi | 10.1371/journal.ppat.1002273 |
| Citation | Ingram JT, et al. (2011) Exhausted CD8 T cells downregulate the IL-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections. PLoS Pathog 7(9):e1002273 |
| abstractText | 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)-gamma 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-gamma 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-alpha (IL-18Ralpha). Although IL-18Ralpha expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Ralpha(lo) exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Ralpha downregulation, we tracked the fate of IL-18Ralpha-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Ralpha 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-18Ralpha(hi) memory cells upregulated CD25 and produced IFN-gamma, the IL-18Ralpha(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. |
