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Wistar scientists find key to keeping killer T cells in prime shape for fighting infection, cancer
Date:11/30/2008

tiviral or antitumor T cell responses, but also to fine tune which response you want to enhance in order to reverse T cell exhaustion and continue fighting an infection or disease.

"This presents us with a great clinical opportunity," Wherry says. "T cells have a lot of weapons at their disposal to control viral infection and most of them are disarmed when these cells become exhausted. It may be possible to selectively rearm T cells while generally reinvigorating them."

The researchers made their discoveries in a mouse model of chronic infection with lymphocytic choriomeningitis virus. They had earlier found 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 a study published September 15 in the Proceedings of the National Academy of Sciences (PNAS), the researchers extended previous studies on the role of the PD-1 pathway in regulating T cell exhaustion. In these studies, blocking PD-1 increased T cell response, but not completely, so the researchers suspected other negative regulatory pathways were activated as well.

In the newest report in Nature Immunology, Wherry and colleagues 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. They are 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 investigators discovered that the severity of chronic infection correlated with the number and intensity of inhibitory rec
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Contact: Staci Vernick Goldberg
sgoldberg@wistar.org
215-898-3716
The Wistar Institute
Source:Eurekalert

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