Protective gene may enhance vaccine responses

Researchers from the University of Chicago have discovered the first of a new class of “protective factors” that appear to be required for the development of memory T cells, the cells that form the core of a vaccine response. The finding could help scientists create more effective vaccines and may lead to potent immune system-based therapies against diseases that have previously eluded vaccines, such as cancer or AIDS.

When the immune system detects an invader, such as a virus, T cells with an affinity for that particular invader multiply rapidly, attack and eliminate infected cells. Once the infection is cleared, however, 90 to 95 percent of those T cells die off, a process called contraction. The five percent or so that survive are known as memory T cells. If a similar infection recurs, these experienced warriors are prepared to rush to the site, recognize that invader and eradicate it again.

Scientists know a great deal about the rapid proliferation and differentiation of these T cells but very little about the factors that regulate contraction. In the September, 2004, issue of Nature Immunology – published on-line August 15 — the researchers show that activation of the gene for the Serine protease inhibitor 2A (Spi2A) can prevent the death of T cells during the contraction phase, resulting in about five times as many memory T cells.

“Drugs based on protective factors such as Spi2A could provide an enormous boost to vaccines,” said study author Philip Ashton-Rickardt, professor of pathology and a member of the committee on immunology at the University of Chicago. “This could allow us to extend the duration of an immune response against chronic infections or to focus the power of the immune system on tumor cells, targets that have thus far been quite elusive.”

The researchers began by screening approximately 11,000 genes from mouse T cells, to find the small number of genes that were more active in the T cells that survived the contraction phase after exposure to a virus. Then they focused on the likely candidates, genes that interfered with the processes that trigger cell death. Their search led them to Spi2A.

Spi2A, they found, was produced in higher amounts in memory T cells. It suppressed cathepsin B, a potent digestive enzyme that can induce cell death. T cell populations in which Spi2A levels were reduced produced fewer memory cells. As a consequence, mice with low Spi2A levels produced a severely diminished response to the virus when exposed to it a second time.

On the other hand, mice with elevated Spi2A produced up to five times the normal number of memory T cells. When faced with the virus a second time, these memory T cells produced an overwhelming response, completely eradicating the infection within hours.

“Spi2A appears to play a crucial role in regulating contraction,” Ashton-Rickardt said. “Increasing Spi2A levels alone can increase the survival of memory T cells from the standard 5 to 10 percent up to about 40 percent.

His lab has already begun to test small molecules that mimic the effects of Spi2A and could be given along with a vaccine.

This finding may also provide clues about how to reverse the process, suggesting ways to reduce or eliminate memory T cells responsible the unwanted immune responses that cause autoimmune diseases such as arthritis.

Additional authors of the paper include Ni Lui, Tiphanie Phillips, Minling Zhang, Yue Wang, Joseph Opferman and Ramila Shah, all from the University of Chicago. The National Institutes of Health funded the study.