July 4, 2009 Interleukin-21 plays a crucial role in fighting off chronic viral infections, three research teams – including one at ETH Zurich – recently concluded. The topic inspired Science to publish three parallel papers in the Science Express. After all, the discovery offers hope for specific treatments against HIV, hepatitis C and B, and tumors.
Chronic viral diseases weaken the immune system: Instead of constantly fighting pathogens over a long period of time, it gives up somewhere along the line. Cytotoxic T lymphocytes (killer T cells), which kill off the infected cells, multiply more than ten-thousandfold during the early stages of a chronic viral disease. During the prolonged fight against the chronic viruses, however, they become exhausted and lose their defense capabilities, or even die off. In the case of HIV, this is the point where AIDS breaks out.
Killer T cells need IL-21
ETH-Zurich scientists from the group headed by Manfred Kopf, a professor at the Institute for Integrative Biology, conducted experiments in mice to find out what causes the killer T cells to crack. “We suspected it had something to do with interleukins”, explains Kopf. These naturally produced messengers of the immune systems control the growth, maturation, differentiation and death of immune cells. We currently know more than 60 of them with different characteristics.
The ETH-Zurich researchers focused on interleukin-21 (IL-21) in their experiments. They used mice that lacked receptors for interleukin-21 on the killer T cells, which meant that the cells were unable to respond to IL-21. The result of the experiment was that the mice were highly susceptible to chronic viral infection. The scientists showed increased exhaustion and death of killer T cells in mice lacking IL-21 receptors during chronic viral infection. The constant supply of IL-21 therefore appears to be crucial for the “fitness” of killer T cells and thus the entire immune system.
Helper T cells form IL-21
The researchers were also able to discover the source of IL-21: It is produced by the helper T lymphocytes (helper T cells). These immune cells support the killer T cells in the fight against chronic viruses. Kopf and his colleagues showed that IL-21 is only essential for defense against chronic viruses, but not for acute viral infections, such as influenza virus. Just how the interaction between helper T cells, Killer T cells and the virus works is still being investigated. Kopf’s team is especially interested in understanding the regulation of IL-21 and IL-21 receptor production during a chronic infection. The group will also look into the question as to whether the amount of IL-21 or the number of IL-21 receptors decides the progression of chronic viral diseases.
IL-21 as a treatment for chronic viral diseases?
The notion of boosting an immune system as it fights a chronic viral infection by giving it IL-21 seems to be the obvious solution. Whether an already exhausted immune system can be revitalized in this way remains unknown, however.
Naturally, the results arouse hopes for the treatment of chronic viral diseases in humans, such as HIV, and hepatitis C or B. IL-21 could also be relevant in combating tumors. After all, killer T cells also fight a long battle here aided by the T helper cells. “Before interleukin 21 can be considered for treatments against chronic viral infections, however, we have to check the extent to which the findings in the mouse model carry over to humans and their viral diseases”, says Kopf cautiously. At any rate, the researchers certainly won’t be short of work.
Fröhlich A, et al. Science. Published online May 28, 2009. Doi: 10.1126/science.1172815
Elsaesser H, et al. Science. Published online May 7, 2009. Doi: 10.1126/science.1174182
Yi J, et al. Science. Published online May 14, 2009. Doi: 10.1126/science.1175194
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