Scientists find key to keeping killer T cells in prime shape for fighting infection, cancer

Nov 30, 2008

Like tuning a violin to produce strong, elegant notes, researchers at The Wistar Institute have found multiple 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 infection- and disease-fighting condition.

In a study published online November 30 in Nature Immunology, the researchers describe their discovery of seven different receptors on T cells that can tamp down immune responses during a prolonged battle with an infectious pathogen or against developing cancer.

Chronic over-stimulation of the immune system can lead to poor control of infections and cancer, so the results explain why it is that these key immune cells gradually become "exhausted" and ineffective over time, says the study's lead author, E. John Wherry, Ph.D., an assistant professor in Wistar's Immunology Program.

Wherry had recently been involved in discovering a single receptor involved in turning off T cells but this new study shows that at least six more receptors can also restrain or negatively regulate immune responses. According to Wherry, a 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.

"This amount of control over T cells' response is remarkable. It suggests that layers of negative regulation exist on exhausted T cells from co-expression of multiple inhibitory receptors," he says. "My bet is that these receptors inhibit different aspects of the T cells' response, but that the net result of their activation is to turn specific T cell populations off.

"We are starting to see a picture emerging of a really tuneable array of inhibitory receptors expressed on T cells," Wherry says. "That suggests it may be possible to not only dramatically enhance antiviral 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 (naïve, 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 receptor expression, suggesting a cumulative impact of inhibitory receptor expression. They also found that blocking both PD-1 and LAG-3 together led to substantially greater improvement in T cell responses and viral control compared to either blockade alone.

"The goal now is to understand the pathways the receptors control, and then to learn how to fine tune reversal of exhaustion by targeting pathways that selectively control the desired type of T cell response," Wherry says.

Source: The Wistar Institute

Explore further: World first prison-based hepatitis C treatment – just one tablet a day

add to favorites email to friend print save as pdf

Related Stories

Tracing water channels in cell surface receptors

Sep 09, 2014

G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in our cells, involved in signal transmission across the cell membrane. One of the biggest questions is how a signal recognized at the extracellular ...

Protein courtship revealed through chemist's lens

16 hours ago

Staying clear of diseases requires that the proteins in our cells cooperate with one another. But, it has been a well-guarded secret how tens of thousands of different proteins find the correct dancing partners ...

Cells put off protein production during times of stress

Sep 11, 2014

Living cells are like miniature factories, responsible for the production of more than 25,000 different proteins with very specific 3-D shapes. And just as an overwhelmed assembly line can begin making mistakes, ...

Recommended for you

Obama's Ebola response: Is it enough and in time?

3 hours ago

President Barack Obama declared Tuesday that the Ebola epidemic in West Africa could threaten security around the world, and he ordered 3,000 U.S. military personnel to the region in emergency aid muscle ...

First domestic case of chikungunya in Brazil

3 hours ago

Brazil's authorities on Tuesday reported the first domestically contracted cases of the mosquito-borne chikungunya virus, prompting the government to announce it was stepping up attempts to control the disease.

Australia promises $6.4 million to fight Ebola

3 hours ago

Australia announced on Wednesday it will immediately provide an additional 7 million Australian dollars ($6.4 million) to help the international response to the Ebola outbreak in West Africa.

User comments : 3

Adjust slider to filter visible comments by rank

Display comments: newest first

tkjtkj
4 / 5 (1) Nov 30, 2008
i'd have rated this more then my '3'
were it not for bad reporting:
".. find the key..." is
completely unsubstantiated by the
article! "Possible key", perhaps.
Junk reporting does no favors for
good science.

E_L_Earnhardt
not rated yet Nov 30, 2008
Computer programers would better understand the functions and malfunctions of the cell, but, alas, chemists control all funding!
Phaze
not rated yet Nov 30, 2008
mass gene sequencing and dedicated peta scale computers are required. AI can find the answers