Nature Immunology mouse study claims blocking PD-1 and LAG-3 together produces better viral control.

Researchers at The Wistar Institute have discovered six new receptors on the outside of the body’s killer immune system cells which they believe can be selectively targeted to keep the cells in superb condition for fighting infection and disease. This important finding could aid T cells during prolonged battles with pathogens, when overstimulation of the immune system causes the cells to become ineffective over time due to exhaustion.

The team had previously established that a receptor known as programmed death-1 (PD-1) was highly expressed by exhausted T cells from chronically infected mice but not from mice that had cleared the infection. In the new study, the investigators found that in mice chronically infected with lymphocytic choriomeningitis virus, blocking in tandem PD-1 and lymphocyte activation gene-3 (LAG-3) substantially improves T-cell response compared to either blockade alone.

The scientists revealed that the severity of chronic infection correlated with the number and intensity of inhibitory receptor expression, suggesting a cumulative impact of inhibitory receptor expression. This result was in line with former research, when blocking PD-1 increased T cell response, but not completely, leading researchers to suspect that other negative regulatory pathways were activated as well.

The team says that one key finding is that these new receptors likely control different aspects of T cell responses, such as division or expansion, controlling viral replication, and local killing of infected cells versus secretion of long-range active antiviral proteins.

“We are starting to see a picture emerging of a really tuneable array of inhibitory receptors expressed on T cells,” said E. John Wherry, Ph.D., an assistant professor in Wistar’s immunology program. “It may be possible to selectively rearm T cells while generally reinvigorating them.”

In the newest report, researchers compared the global patterns of gene expression for exhausted killer T cells compared to other types of T cells (nave, effector, and memory). A nearest neighbor analysis to PD-1 revealed up-regulation of six other inhibitory receptor genes: LAG3, 2B4, CD160, CTLA-4, PIR-B, and GP49. While the function of many of these receptors has been characterized, they had not been known to play a role in chronic viral infection. LAG-3, for example, is associated with an antitumor response. These observations may explain why PD-1 blockade did not completely restore T-cell responses in previous work.

The study was published online November 30 in Nature Immunology.

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