PD-1 Pathway Does Not Cause T-Cell Exhaustion, Scientists Show

Sometimes even cells get tired. When the T cells of your immune system are forced to deal over time with cancer or a chronic infection such as HIV or hepatitis C, they can develop what is termed “T cell exhaustion,” becoming less effective and losing their ability to attack and destroy the invaders of the body. While the PD-1 protein (programmed cell death protein 1) pathway has long been implicated as a primary player in T cell exhaustion, a major question has been whether PD-1 actually causes exhaustion directly. A new paper from the laboratory of E. John Wherry (photo), Ph.D., a Professor of Microbiology and Director of the Institute for Immunology, in the Perelman School of Medicine at the University of Pennsylvania, seems to, at least partially, let PD-1 off the hook. The paper was published online on June 1, 2015 in the Journal of Experimental Medicine. The article is titled “Genetic Absence of PD-1 Promotes Accumulation of Terminally Differentiated Exhausted CD8+ T Cells.” 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 has been 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 anti-viral and anti-tumor responses in animal models,” Dr. Wherry notes. “But a key question has been whether this PD-1 pathway causes exhaustion. Our work shows that it does not.” Dr. 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.
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