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TSRI Scientists Identify Protein Behind Immune System ‘Shut Down’

Findings Suggest New Drug Target for Cancer, Chronic Infections

LA JOLLA, CA – October 31, 2016 – In a new study with broad implications for treating cancers and chronic viral infections, scientists at The Scripps Research Institute (TSRI) have uncovered a mechanism behind a phenomenon called “T cell exhaustion.” T cell exhaustion occurs when the body damps down the immune system once it realizes a virus or tumor has the upper hand—in HIV infections, for example.

The scientists’ research points to a specific protein that works to cripple the immune system’s T cells in these cases, hampering the body’s ability to respond over the long-term to chronic conditions.

“This might have important implications for HIV and tumor immunity,” said TSRI Professor Linda Sherman, who was senior author of the new study.

The study, published the week of October 31, 2016 in the journal Proceedings of the National Academy of Sciences, focused on a protein called PTPN22.

Harnessing T Cells

Sherman and her colleagues knew that PTPN22 was expressed in all immune cells, and that individuals that expressed an altered form of the PTPN22 protein had significantly increased risk for type 1 diabetes and many other autoimmune diseases—signs of an overactive immune system.

“T lymphocytes are very destructive, so if the virus is there to stay, the body wants the immune system to shut off to stop doing damage to the organism,” said Sherman.

This led the researchers to wonder: Could deficiency of this protein work in reverse to prevent the immune system from establishing T cell exhaustion?

Sherman and her colleagues tested this hypothesis by infecting mouse models with a clone of lymphocytic choriomeningitis virus (LCMV), which causes chronic infections similar to HIV and hepatitis.

The researchers found that mice without PTPN22 were able to clear LCMV infections, while mice with PTPN22 showed chronic infection and signs of T cell exhaustion.

“The animals deficient in the PTPN22 protein shrugged off the virus very quickly, rather than having the immune system shut down the way it normally does when it encounters this virus,” said Sherman.

Next, the researchers took a closer look at the mechanisms that made this defense possible. They found that PTPN22 in certain immune cells increases the production of an immune system molecule called interferon beta, which in turn increases the production of a protein called CREM. This leads to the depletion of interleukin 2, an anti-inflammatory molecule crucial to T cell function.

Removing PTPN22 from this system keeps T cells functioning. This explains why animal models with the inactive allele of the PTPN22 gene can better fight LCMV.

This finding could also provide an evolutionary reason why so many people—about 10 percent of the U.S. and European populations—have the inactive PTPN22 allele. While they have increased risk for autoimmune disease, the tradeoff may be a better ability to fight off chronic infections.

“There’s still so much to learn about the immune system,” said Sherman.

The team’s next step will be to study PTPN22’s role in more kinds of cells. “We have to understand what’s going on so we can take advantage of that to make new types of drugs,” Sherman said.

In addition to Sherman, authors of the study, “PTPN22 contributes to exhaustion of T cell lymphocytes during chronic viral infection,” included Christian J. Maine, John R. Teijaro and Kristi Marquardt, all of TSRI at the time of the study.

The study was supported by the National Institutes of Health (grants AI119353 and 1R01AI123210).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

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Linda Sherman is a professor at The Scripps Research Institute. (Photo by Michael Balderas.) (High-res image)


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