Blocking PD-1 Receptors Revitalizes T Cells

Researchers have identified the mechanism that causes the immune system's main line of defense, CD8 T cells, to become tolerant of chronic viral infections and have found a way to revitalize them and return them to the fray.

Investigators at the Dana Farber Cancer Institute (Boston, MA, USA) and Emory University (Atlanta, GA, USA) worked with a mouse model. They used a microarray system to analyze the genome of "exhausted” CD8 T cells from animals infected with chronic lymphocytic choriomeningitis virus (LCMV). The gene scan was compared to that obtained from CD8 T cells from normal mice. They found that the PD-1 gene was much more active in the exhausted cells. This result was in accord with previous findings that binding of PD-L1 protein by the PD-1 receptor caused a weakening of immune system response.

Monoclonal antibodies were prepared that bound specifically to the PD-1 receptor and prevented the binding of PD-L1. These antibodies were administered to both chronically infected wild type mice and to mice lacking CD4 T "helper” cells. Results published in the December 28, 2005, online edition of Nature showed that in both cases, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the "helpless” CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells, and decrease viral load. Blocking the CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitory pathway had no effect on either T cell function or viral control.

"The potential applications of this work are wide-ranging,” said contributing author Dr. Gordon Freedman, associate professor of medicine at the Dana Farber Cancer Institute. "CD8 T cells that have fought viral infections retain a ‘memory' of the viruses they have encountered, so they can rapidly respond to new infections from those viruses. 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.”




Related Links:
Dana Farber Cancer Institute
Emory University