A basic science discovery concerning how part of the immune system remembers past opponents may provide the solution to a fundamental problem facing vaccines to treat AIDS or cancer. Researchers from the University of Chicago report in the March 12 issue of the journal Science that the cells that are crucial players for any vaccine against HIV-infected or cancerous cells are distressingly slow learners.
The problem, the researchers demonstrate, is that it takes several generations of intense instruction to make a lasting impression on a T cell. Creating large numbers of "memory" T cells that can recognize a trouble maker they have seen before and attack when they see it again requires prolonged continuous exposure to high levels of the intruder.
"This finding suggests that the typical approach to vaccines for treatment of cancer or AIDS is not often likely to produce the desired result," said author Philip Ashton-Rickardt, Ph.D., assistant professor of pathology at the University of Chicago. "But it also shows us how we can get around the problem."
Ashton-Rickardt's team -- including immunology graduate student Joseph Opferman and post-doctoral fellow Bertram Ober, Ph.D., all from the Gwen Knapp Center for Lupus and Immunology Research at the University of Chicago -- set out to answer a central question in immunology: Where do the T cells responsible for "remembering" a previous infection and fighting it off a second time come from?
When stimulated by an invader, T lymphocytes multiply and attack the infecting foreigner. Once they get the upper hand, most of these T cells are no longer needed and die off. A small percentage, however, survive and stand guard in case this particular invader comes back.
Immunologists have proposed two models of this process. One requires two parallel tracks for cell-killing T lymphocytes. Most of the T cells attack the foreigner then die off soon after victory. But a smaller group of T cells is preprogrammed to survive and to remember the invader. B lymphocytes, the immune cells that secrete antibodies, follow this pattern.
The competing model involves just one initial population of cell-killing T cells. Most of these cells die off after defeating the invader, but some cells survive and develop into memory cells which remain eternally vigilant for any subsequent attack.
The research team confirmed the second model. They found that it required intense, prolonged stimulation -- high levels of antigen for at least five cell divisions -- to create a significant number of memory T cells. Without strong stimulation for three to four days, few memory cells emerged. By finding the answer to this fairly basic scientific question, "we have stumbled into the world of clinical relevance," jokes Ashton-Rickardt.
"No vaccine trial to date," he said, "has been able to produce significant numbers of memory T lymphocytes, which are important in killing HIV-infected or cancerous cells. Now we know why, and we have a pretty good idea of how to change that."
The research team, working with mice, grew the memory T cells outside the body, which enabled them to challenge the cells constantly with high levels of antigen for four-to-five days -- a far more intense and prolonged confrontation than any vaccine scheme.
To test the effects, they injected the activated cells into mice without immune systems. Ten weeks later, the injected T cells were still effective, retaining all their cell-killing machinery.
"The great thing was that the memory cells were primed and ready. They required no help from other cells -- no cytokines, no co-stimulation," said Ashton-Rickardt. "They remembered and went after their targets as soon as they were exposed to them again. Although mice with normal immune systems take two or three days to mount an immune response, these memory T cells responded immediately."
The finding is particularly encouraging for those interested in vaccines as therapy for HIV infected patients, who lose their T-helper cells. Ordinarily, chemical signals from these T-helper cells are required to activate cytotoxic T cells, which are not damaged by HIV. But by growing cytotoxic T memory cells outside the body and exposing them to specially presented HIV antigens, this approach should produce effective cytotoxic T cells, which could destroy HIV-infected cells.
"We have the technology to try this already," explained Ashton-Rickardt. "Perhaps now we know how to use it."
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Science