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Molecular Signal Guides Immune Cell Action

Johns Hopkins Kimmel Cancer Center researchers have found that a signaling molecule called mTOR plays a crucial role in directing immune system T cells toward specific disease-fighting functions.

The work, published in the June 19 issue of the journal Immunity, suggests that mTOR and other proteins affected down the line by its signals could serve as potential pharmacologic targets to promote immunity in diseases such as cancer.

T cells normally integrate and respond to a broad array of environmental signals. When activated, they decide what type of cell to change into to best do a necessary job. For example, Th1 cells help fight cancer or viruses, Th2 cells help fight parasites but also promote allergy and asthma, and Th17 cells help fight bacterial infections.

The Hopkins study demonstrates that mTOR (mammalian target of rapamycin), a protein that regulates various cell functions such as growth, motility and survival, helps dictate the outcome of T cells. For the study, senior author Jonathan D. Powell, M.D., Ph.D., an associate professor of oncology, and colleagues created genetically engineered mice in which mTOR was specifically deleted from T cells. Various laboratory experiments revealed that without mTOR, the cells were unable to change into the various T helper cells. Instead, they became regulatory cells, which inhibit the activation of immune cells, preventing too strong an immune response.

“Our work suggests that mTOR signaling regulates the decision toward which type of cell that T cells become,” Powell says. “Without mTOR, T cells default to become regulatory cells, so signals leading to the activation of mTOR are required to redirect the cells toward active immunity.”

The research already has led to the development of a novel approach to curing sickle cell disease with bone marrow transplantation. In addition, it has spurred the development of three cancer clinical trials at Hopkins, Powell says. In the first, physicians David Loeb and Katherine Thornton will investigate if inhibiting mTOR can hinder cancer stem cells in sarcoma patients. For the second, physicians Douglas Gladstone and William Matsui are investigating the use of mTOR inhibitors in mantle cell lymphoma. In the third, physician Ivan Borello will use an inhibitor of mTOR to try to preserve bone in multiple myeloma patients.

The work was supported by the National Cancer Institute and the National Institute for Allergy and Infectious Diseases. Coauthors were Greg M. Delgoffe, Thomas P. Kole, Yan Zheng, Paul E. Zarek, Krystal L. Matthews, Bo Xiao, and Paul F. Worley of Hopkins; and Sara C. Kozma of the University of Cincinnati, Ohio.


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