Study Investigates Molecular Events That Control Immune Memory

The results of a new University of Iowa study challenge an old assumption about how the immune system responds to an infection and could have important implications for improving vaccine efficiency. The study appears online in Nature Immunology (advance of print publication at http://immunol.nature.com) on June 3.

The ability of the immune system to remember infections it has already defeated, and to respond rapidly and effectively to them during future exposures, is the basis of vaccination strategies. This immune memory is the result of a complex set of molecular events that John Harty, Ph.D., UI associate professor of microbiology, and his colleagues are investigating.

Prior to infection or vaccination, the immune system contains a diverse reservoir of immature T cells. This large population of cells is composed of thousands of subgroups, each able to recognize different pathogens such as bacteria and viruses. When the system encounters a specific infection, the group of T cells that recognize that particular infection is rapidly mobilized. Over the space of several days, this population of cells expands from a few thousand to millions of cells, which then mature, developing the capability to fight off the infection. Finally, around 90 percent of the cells die off, leaving the remaining 10 percent as memory cells that maintain life-long protection against reinfection.

"This contraction of the T cell response is important as it sets the memory level. It also prevents T cells specific for only a single infection from taking over the immune system and hindering responses to new infection," Harty said. "Immunology textbooks teach that contraction occurs when the infection is cleared, suggesting that the immune system 'senses' this change and responds accordingly. In contrast, our work demonstrates that contraction of the T cell response is not linked to clearance of infection."

The UI researchers examined the timing and rate of T cell contraction during infections in mice. Various strategies were used to alter the duration of infection. In one experiment, mice infected with bacteria were given antibiotics to artificially shorten the duration of the infection. To study the alternative situation where an infection persists, the researchers used genetically modified mice that are unable to clear a viral infection. In both cases, the "die-off" stage of T cells followed the same pattern and timing. These experiments showed that T cell contraction is independent of whether an infection is still present. The results were similar for both bacterial and viral infections.

Harty explained that the finding that the contraction is "preprogrammed" could have implications for improving vaccine design.

"The immune response that we are studying is a very long and complicated process, and the cells go through many phases," Harty said. "But it looks like those phases are all controlled from the very beginning; the expansion, and the contraction to memory levels, seem to be programmed before they know whether they are going to win the battle against the infection. If we can learn how to optimize the early events, then we should be able to improve the efficiency of vaccines."

Vaccines essentially trick the immune system into thinking that it has been infected so that it remembers that infection. The memory cell population is the goal of vaccination; these cells provide protection from reinfection. There is a direct relationship between the number of memory cells and the degree of protection achieved. Therefore, a weak vaccine may only cause a small expansion of T cells.

"When only 10 percent of a small expansion population survives, that memory population might not be sufficient to help defend against the disease or to provide long-term protection," Harty explained. "If we were able to boost the percentage of memory cells that survive from the expansion, that might make the first vaccination last longer and be more efficient."

Although vaccines are designed to be as safe as possible, there can be unpleasant and even dangerous side effects. Thus, reducing the number of vaccinations required to generate immunity would be beneficial.

Although the size of the initial T cell expansion directly affects the final size of the memory cell population, the UI researchers discovered that the timing and rate of the T cell die-off phase was not influenced by the size of the initial T cell expansion.

The team investigated factors that might control the size of the T cell expansion. They found that the expansion was dependent on the strength of the initial infection. If the immune system was challenged with a large dose of virus or bacteria, then a large population of T cells was generated by the expansion phase.

The size of the T cell expansion also depends on how much of the pathogen is presented to the immune system. This aspect of the immune response process is called antigen presentation and is difficult to quantify. The UI team developed a very sensitive method for measuring antigen presentation and was able to prove that the level of infection and the amount of antigen displayed or presented to the immune system are linked.

"Our work is the basic science of understanding what regulates the T cell response," Harty said. "We hope that insights from our research could be used to improve vaccine efficiency."

In addition to Harty, the UI research team includes Vladimir Badovinac, Ph.D., UI postdoctoral fellow in microbiology, and Brandon Porter, a graduate student in the UI interdisciplinary program in immunology.

The study was funded in part by grants from the National Institutes of Health and a fellowship from the Leukemia and Lymphoma Society.