Exhausted cd8 t cells downregulate the il-18 receptor and become unresponsive to inflammatory cytokines and bacterial co-infections

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. © 2011 ingram et al.