Like boxers wearied by a 15-round bout, the immune systems CD8 T cells eventually become exhausted in their battle against persistent viral infection, and less effective in fighting the disease.
In a study to be published Dec. 28, 2005 on the journal Natures Web site, researchers at Dana-Farber Cancer Institute and Emory University have traced the problem to a gene that turns off the infection-fighting drive of CD8 T cells in mice. The discovery raises the possibility that CD8 cell exhaustion can be reversed in human patients, reinvigorating the immune systems defenses against chronic viral infections ranging from hepatitis to HIV, the virus that causes AIDS.
CD8 T cells that have fought viral infections retain a memory of the viruses theyve encountered, so they can rapidly respond to new infections from those viruses, says the studys author, Gordon Freeman, PhD, of Dana-Farber. In the case of chronic infection, however, senior author Rafi Ahmed, PhD, of Emory, has shown that memory cells become exhausted and lose the capacity to respond to the virus. Why this occurs, on a molecular level, has been unclear.
To find the cause, Freeman and his colleagues conducted a microarray experiment measuring the activity of thousands of genes in normal memory CD8 T cells in mice and in exhausted versions of those cells. They found that a gene known as PD-1 was much more active in the exhausted cells.
From previous research, Freemans team knew that PD-1 is responsible for a specialized receptor in CD8 cells -- a tiny socket for receiving signals from other cells. In 2001, Freeman and his colleagues showed that when the PD-1 receptor latches onto a molecule called PD-L1, the immune systems response to infection is weakened. Freemans team made antibodies to block this interaction.
When [co-author] John Wherry of the Wistar Institute found a high level of the PD-1 gene in microarray experiments, we wanted to test whether this was contributing to the CD8 exhaustion, says Freeman, who is also an assistant professor of medicine at Harvard Medical School. We found that exhausted CD8 T cells in mice have unusually large numbers of PD-1 receptors, and blocking the PD-1/PD-L1 bond reactivated the cells response to infection.
Just as strikingly, researchers found that even in persistently infected mice that lacked a type of T cell known as helper CD4, preventing PD-1 from binding to PD-L1 had a beneficial effect on helpless CD8 T cells -- restoring their ability to kill infected cells and release infection-fighting substances called cytokines, substantially reducing the animals viral load.
Although its not known why CD8 cells become exhausted -- roughly a month after infection begins -- scientists theorize that it may be part of the bodys system for naturally ending the immune response after an infection has been quelled. If it persists too long, the immune response can damage normal, healthy tissue. In the mouse studies, CD8 T cells were reinvigorated only as long as researchers continued to administer PD-1/PD-L1 blockers, so the chance of sparking a runaway immune response seems unlikely.
If human CD8 T cells are found to operate by a mechanism similar to that in mice, the new findings may offer a simple immunological strategy for treating chronic viral infections. Freemans lab is also exploring whether anti-cancer T cells become exhausted in various types of tumors and in HIV-infected individuals.
The potential applications of this work are wide-ranging, Freeman remarks, noting that he and his collaborators have recently received a grant from the Bill and Melinda Gates Foundations Grand Challenges in Global Health program to extend their findings to hepatitis C infection.
The studys first author is Daniel Barber, PhD, of Emory University School of Medicine.
In addition to Freeman, Ahmed and Wherry, the studys other authors are David Masopust, PhD, of Emory; Baogong Zhu, MD, of Dana-Farber; James Allison, PhD, of Memorial Sloan-Kettering Cancer Center in New York; and Arlene Sharpe, MD, PhD, of Brigham and Womens Hospital in Boston.
The research was supported in part by the Bill and Melinda Gates Foundations Grand Challenges in Global Health initiative, the National Institutes of Health, Howard Hughes Medical Institute, and Cancer Research Institute.
Source: Dana-Farber Cancer Institute