Yale Researchers Uncover Cellular Intricacies That Could Lead to Better Vaccines

In research that could lead the way to development of stronger vaccines and better therapy against tumors and autoimmune diseases, a team of researchers from Yale School of Medicine has shown how blocking a protein that controls cellular growth and death increased the number and lifespan of disease-fighting immune cells. They also reveal how a key component of cellular signaling may help in this increased effectiveness. The research, which was conducted using laboratory mice, is published in the July issue of “Immunity.”

The researchers set out to study the delicate interplay between Transforming Growth Factor Beta (TGF-β) and the cellular signaling molecule Interleukin-15 (IL-15) in controlling the effectiveness of Cytotoxic T cells (CD8+ T-cells) in killing tumor cells and cells infected with viruses and bacteria. They infected mice with Listeria bacteria and studied the cellular reaction in the acute infection that resulted, and in the immunity that built up over the next few days.

They found that when they blocked TGF-β signaling, many more CD8+ cells survived, helped by IL-15, and this increased lifespan was accompanied by a greater number of “memory cells” which are necessary for lasting immunity against disease.

Lead author Richard A. Flavell, Ph.D., of Yale School of Medicine and the Howard Hughes Medical Institute, says, “This was a key discovery in understanding how to increase the quantity and life span of effector CD8+ T cells to confer greater, long-lasting protection against disease.”

How might this lead to stronger vaccines and tumor-fighting therapies? Co-author Shomyseh Sanjabi, Ph.D., says, “Pharmacological agents are being developed that, if administered as vaccines, can block TGF-β signaling and cause a boost in the expansion of effector CD8+ T cells. This would create more long-lasting memory cells. Similar approaches are also being taken to block TGF-β signaling to improve the life span of tumor-fighting effector CD8+ T cells.”

The third author was Munir M. Mosaheb, M.S., of Yale School of Medicine.

The research was funded by grants from the Cancer Research Institute, the National Institutes of Health and the Juvenile Diabetes Research Foundation and support by the Howard Hughes Medical Institute.

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Helen Dodson: helen.dodson@yale.edu, 203-436-3984