Sometimes even cells get tired. When the T cells of the immune system are forced to deal with cancer or a chronic infection such as HIV or hepatitis C over time, they can develop T cell exhaustion and become less effective and lose their ability to attack and destroy the invaders of the body.

While the PD-1 protein pathway has long been implicated as a primary player in T cell exhaustion, a major question has been whether PD-1 actually directly causes exhaustion. A new study seems, at least partially, to let PD-1 off the hook. It was published in the Journal of Experimental Medicine (2015; doi:10.1084/jem.20142237).

In short-term infections such as a cold or flu, PD-1 helps to regulate an initial strong T cell response, preventing the T cells from over proliferating and attacking the body’s own cells after the infection is cleared. But in patients with cancer or chronic infections, blocking PD-1 has proved a highly successful therapeutic strategy that allows the T cells to fight on.

“Blocking this pathway reverses T cell exhaustion and improves tumor immunity in humans and antiviral and antitumor responses in animal models,” said corresponding author E. John Wherry, PhD, a professor of microbiology and director of the Institute for Immunology in the Perelman School of Medicine at the University of Pennsylvania. “But a key question has been whether this PD-1 pathway causes exhaustion. Our work shows that it does not.”

Wherry and his collaborators used PD-1 knockout mice infected with lymphocytic choriomeningitis virus to see whether the genetic deletion of PD-1 would be enough to prevent T cell exhaustion. They observed a robust initial T cell response, but with a cost.

“While transient disruption of this pathway may have therapeutic benefit because it temporarily revs up the immune response, permanent loss of PD-1 signals seems to result in a flame out where T cells can’t sustain higher level activation and become more dysfunctional,” Wherry said.

After a month or so, he explained, “the advantages in proliferation and other signaling pathways that cells had without PD-1 go away.”

Without the regulatory influence of PD-1, the overactivated and overstimulated T cells result in disruption of a crucial balance between different T cell types that leads to an overall greatly reduced immune response.

The work demonstrates that even with the clinical successes of blocking PD-1, there may be a better, more refined therapeutic strategy to target the PD-1 pathway.

“We know that transient blockade has tremendous benefit,” Wherry said. “But we also knew that there are subtypes of exhausted T cells that can or cannot be revitalized by transient PD-1 blockade. Our new work shows that PD-1 signals help regulate this balance.”

In effect, PD-1 may actually help to preserve a reserve force of T cells that can fight on later in the long-term cellular war between the immune system and foreign invaders or tumors.