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Protein MCL1 Prevents Cell Death to Prolong Anti-virus Response

May 07, 2015
Lebanon, NH

The mechanisms of long-term immunity from viruses that we’ve fought off may be key to protection against cancer, according to a study led by Dartmouth’s Norris Cotton Cancer Center investigators Edward Usherwood, PhD, Ruth Craig, PhD, Ethan Dmitrovsky, MD, and Jingang Gui, PhD. Their findings were published in the Journal of Virology , and titled, “MCL1 enhances the survival of CD8+ memory T cells after viral infection.”

“Cells that make up your long-term immune response don’t just passively persist for years to protect you,” explained Usherwood. “They have mechanisms that actively keep them from the normal cell death cycle. This allows them to survive long enough to protect you for years, or even decades.”

Viral infections generate massive amounts of activated effector CD8(+)T cells that recognize viral components. Generally, these cells die after just one encounter with a virus, but a small population survives to protect us by creating antigen-specific cells that remember the virus and how to fight it, even over long periods of time.

The Dartmouth group used mice engineered to express a human form of the protein MCL1 produced T cells. This exhibited a better memory response , indicating MCL1 is important for long-term T cell immunity. They studied the T cell response to vaccinia virus infection because it induces a very potent cytotoxic T cell response.

“Our findings are applicable to other conditions that involve T cell immunity, such as other virus infections and the T cell responses that protect against cancer,” said Usherwood. “By their very nature, studies on T cell memory take a long time. We measure quite small populations of cells, which requires very sensitive analysis by flow cytometry in order to interrogate their function.”

To focus on only those T cells responding to the virus and examine them in detail, the team used Dartmouth’s Flow Cytometry Shared Resource.  “By using the Flow Cytometry Shared Resource we were able to accomplish investigation that would have been prohibitively expensive if we had to purchase all of the investigational equipment,” Usherwood said. Dartmouth’s Shared Resources are open to outside investigators by arrangement.

Looking forward, the team plans to test manipulation of MCL1 levels in T cells using drugs, or immune-stimulating adjuvants, as this may be a way to produce better memory responses using vaccines or immune therapy.

The research team members are on the faculty of Dartmouth’s Geisel School of Medicine where Usherwood is Professor of Microbiology & Immunology; Craig and Dmitrovsky are Professors of Pharmacology & Toxicology; and Gui was previously a post-doctoral fellow. Their work in cancer is facilitated by Dartmouth’s Norris Cotton Cancer Center where Usherwood is a member of the Immunology & Cancer Immunotherapy Research Program; Craig and Dmitrovsky are members of the Molecular Therapeutics Research Program.

This work was supported by National Institutes of Health grants AI069943, CA103642 to Usherwood, CA057359 to Craig, and CA062275 to Dmitrovsky. 

About Norris Cotton Cancer Center at Dartmouth-Hitchcock

Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute's "Comprehensive Cancer Center" designation. Learn more about Norris Cotton Cancer Center research, programs, and clinical trials online at cancer.dartmouth.edu.

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