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-18Rαlo 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-18Rαhi memory cells upregulated CD25 and produced IFN-γ, the IL-18Rαlo 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

Identifying change over time in small area socio-economic deprivation

The measurement of area level deprivation is the subject of a wide and ongoing debate regarding the appropriateness of the geographical scale of analysis, the input indicator variables and the method used to combine them into a single figure index. Whilst differences exist, there are strong correlations between schemes. Many policy-related and academic studies use deprivation scores calculated cross-sectionally to identify areas in need of regeneration and to explain variations in health outcomes. It would be useful then to identify whether small areas have changed their level of deprivation over time and thereby be able to: monitor the effect of industry closure; assess the impact of area-based planning initiatives; or determine whether a change in the level of deprivation leads to a change in health. However, the changing relationship with an outcome cannot be judged if the ‘before’ and ‘after’ situations are based on deprivation measures which use different, often time-point specific variables, methods and geographies. Here, for the whole of the UK, inputs to the Townsend index obtained from the 1991 and 2001 Censuses have been harmonised in terms of variable detail and with the 1991 data converted to the 2001 Census ward geography. Deprivation has been calculated so that the 1991 scores are directly comparable with those for 2001. Change over time can be then identified. Measured in this way, deprivation is generally shown to have eased due to downward trends in levels of lack of access to a car, non-home ownership, household overcrowding but most particularly, to reductions in levels of unemployment. Despite these trends, not all locations became less deprived with gradients of deprivation largely persisting within the UK’s constituent countries and in different area types. For England, Wales and Scotland, the calculation of Townsend scores can readily be backdated to incorporate data from the 1971 and 1981 Censuses to create a 1971–2001 set of comparable deprivation scores. The approach can also be applied to the Carstairs index. Due to differences in data availability prior to 1991, incorporating small areas in Northern Ireland would be challenging