The prevalence of viruses like HIV and Hepatitis C, which cause chronic infections, raises questions about the long-term effects of infection on the immune system. These questions include: How does the immune system’s composition change in response to a chronic infection? How do the immune system’s effector functions change? How is a defense mounted against other simultaneous infections? In a recent PLoS Pathogens article, Zajac and coworkers address some of these questions. They describe a population of cells, called exhausted T cells, which develop from chronic viral infection and have a reduced ability to fight bacteria.
The presence of an intracellular pathogen, like a virus, rallies a population of T cells to combat the virus. Among the cells produced are effector and memory CD8+ T cells. Effector CD8+ T cells are capable of lysing (killing) cells infected with the same virus that induced their production. Memory CD8+ T cells, on the other hand, wait for further stimulation (a second infection with the same virus) to proliferate and produce the next generation of effector cells. These functions constitute an adaptive response, where T cells respond to one antigen (the virus) specifically.
In addition, effector and memory CD8+ T cells can mount a broader innate-like response that does not require the presence of the specific antigen that induced their production. For example, if effector or memory CD8+ T cells receive cytokines (molecular signals) IL-12, IL-18, and IL-21, produced in response to an infection, they can secrete a cytokine called IFN-gamma that helps other cells take action against the infection. Here the memory and effector cells are responding not to one antigen, but any antigen that induces production of IL-12, IL-18, and IL-21.
While it was already known that exhausted T cells, produced from persistent viral infection (think: less effective versions of effector/memory cells), mount weaker adaptive responses than normal effector or memory T cells (2), Zajac and coworkers found that exhausted T cells mount weaker innate-like responses, as well.
In their study, Zajac and coworkers infected different types of mice with different types of lymphocytic choriomeningitis virus (LCMV) to produce three unique responses. One combination produced an acute infection, which gave rise to effector and memory cells; a second produced a protracted infection, which gave rise to effector and exhausted cells; and a third produced a chronic infection, which gave rise to predominantly exhausted cells.
Upon addition of IL-12, IL-18, and IL-21 individually, effector and memory cells produced only modest amounts of IFN-gamma. Upon addition of different combinations of these cytokines, including, IL-12/IL-18, IL-18/IL-21, and IL-12/IL-18/IL-21, memory and effector cells produced high levels of IFN-gamma. The same combinations of cytokines, however, did not induce exhausted T cells to produce IFN-gamma.
A study of cell surface proteins revealed that the exhausted cells have similar expression of IL-12R-beta-2, a receptor for IL-12, higher expression of IL-21R, a receptor for IL-21, and lower expression of IL-18R-alpha, a receptor for IL-18, compared to memory and effector cells. The lower expression of IL-18R-alpha explains exhausted cells’ inability to produce IFN-gamma in response to the combinations of cytokines used in this study, all of which included IL-18. In addition, Zajac and colleagues observed preferential deletion of exhausted cells. This result also makes sense in light of the decreased expression of IL-18R-alpha, which is thought to be a receptor for a “survival signal” necessary for warding off cell death (3). Without the proper receptor, the signal cannot be received, and the cell may die.
The researchers also introduced Listeria monocytogenes (LM), a bacterium that induces IL-12 and IL-18 production, to populations of LCMV-derived effector, memory, and exhausted T cells. Only effector and memory cells, which have higher IL-18R-alpha expression, produced IFN-gamma. This result suggests that the presence of a chronic viral infection leads to a weaker T cell response against a concurrent bacterial infection. Thus, not unlike the Tregs discussed in my last blog, it appears that exhausted T cells might both protect the body from too vigorous a response, yet allow infections to persist. Interestingly, the researchers observed that the bacterial infection was eventually brought under control, suggesting that other immune system components compensate for the weakened T cell response, though the exact mechanism of this support is unknown and ripe for future study.
By investigating an example of concurrent chronic viral and bacterial infection, this study illustrates the complex interactions of innate and adaptive immunity, as well as the complex interaction of one immune response on another. Zajac and coworkers thus demonstrate the need not only further for investigation of the effects of exhausted T cells on the immune response but also for further investigation of the interplay of immune responses to multiple simultaneous infections.
Ingram J.T., Yi J.S., Zajac A.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): e1002273. doi:10.1371/journal.ppat.1002273
(2) Mackerness K.J., Cox M.A., Lilly L.M., Weaver C.T., Harrington L.E., et al. (2010). Pronounced virus-dependent activation drives exhaustion but sustains IFN- gamma transcript levels. J Immunol. 185: 3643–3651.
(3) Li W., Kashiwamura S., Ueda H., Sekiyama A., Okamura H. (2007). Protection of CD8+ T cells from activation-induced cell death by IL-18. J. Leukoc. Biol. 82: 142–151.