Several viruses are known to cause chronic infections, one is hepatitis C virus (HCV). Researchers studying chronic viral infections have now found that when they occur, immune cells known as killer T cells can become exhausted, and enter a state of dysfunction in which they stop reacting to infectious disease like they normally do. Killer T cells are normally on the front lines of immune defense, and when they wear out, they start to act more like different immune memory cells. These findings have been reported in Nature Immunology. Another study in the same journal has identified potential approaches to relieve these exhausted cells and restore their killer functions.
In one study, investigators assessed the differences between exhausted T cells and memory cells before and after the patients' HCV infections were successfully treated. The research suggested that after the infection was cured, T cells that had been exhausted by the infection took on some of the characteristics of memory T cells, but they weren't functioning well.
"We saw some cosmetic improvement of the T cells that in a more superficial study could have been interpreted as real recovery, whereas in reality the key parameters determining the efficacy of a T cell were unchanged," explained the senior author of this study, Georg M. Lauer, M.D., Ph.D., of the Division of Gastroenterology at MGH. "A significant number of molecules that were altered were normalized after treatment, but others were stuck, and these were clearly the ones associated with T cell function."
The longer that T cells had been activated by the viral infection, the more pronounced the lack of recovery became. But T cells that were stimulated for a shorter time period were able to act like functional memory T cells.
Now the researchers are investigating whether an antiviral therapy that acts directly during the acute phase of infection will create memory T cells. This approach would shorten the window in which treatment could be applied to a chronic infection if T cell function is to be protected, noted Lauer.
It may be possible to rescue severely exhausted T cells as well by targeting the molecules that change as the cell wears out.
The other Nature Immunology study determined that in T cells exhausted by a chronic HCV infection, there were epigenetic changes that altered gene expression. When the virus was treated, some of the epigenome was rescued, but other aspects of the epigenome retained some of the changes they'd taken on when the T cells were exhausted by the infection. The authors called these residual alterations 'epigenetic scars.' This work agreed with the other study, and suggested that epigenetics are involved in the determining T cell fate.
"These scars might be locking the exhausted T cells and preventing return to proper function even if the chronic infection in the patient is cured," noted senior study author Debattama Sen, Ph.D., of the Center for Cancer Research at MGH. "Thus, restoring the function of these cells will likely require directly removing or inactivating these scarred regions to unlock the cells' functionality."
The researchers assessed T cells during the course of viral infections that were cleared, like influenza, and others that were chronic, like HCV and HIV, to create a map of epigenetic scars related to T cell exhaustion. The researchers are hopeful that this will show scientists where repairs could be made with gene-editing in exhausted T cells.