A highly contagious bacterial infection that primarily affects the lungs, tuberculosis is responsible for two million deaths each year and affects an estimated 16 million people around the world.
“Tuberculosis is a huge killer internationally,” says study co-author Norman L. Letvin, M.D., Chief of Viral Pathogenesis at BIDMC and Professor of Medicine at Harvard Medical School. “Worldwide, the major targets for vaccine development are the HIV virus, tuberculosis and malaria. Anything that moves us even a little closer to these vaccines is very important.”
The existing TB vaccine – created in 1908 and first used in 1921 – has proven successful in protecting children from the disease, but has had varied effectiveness in adults.
In the new study, lead author Zheng Chen, M.D., of the BIDMC Tuberculosis Research Unit and colleagues used macaque monkeys to study the nature of the immune responses of gamma delta T cells, a group of white blood cells that were first identified several years ago, and make up a significant component of the body's immune system.
When battling infectious agents – including viruses, bacteria, fungi and all other pathogens – the immune system relies on two separate types of immune responses: innate immunity and acquired immunity. T cells with innate immunity, including the gamma delta T cells, function as the immune system's “first line of defense” against foreign microbes, kicking in within hours of infection and temporarily “stunning” the microbes into submission, according to Letvin.
T cells that are part of the acquired immune response then take center stage, playing a crucial role in eliminating foreign pathogens once an infection has developed. Acquired immunity takes time to mature – anywhere from days to weeks – but is the more effective of the two immune responses because it not only recognizes and attacks specific protein sequences of the foreign “intruder,” it also remembers them. “Once the initial infection has been contained, this population of T cells switches roles and becomes ‘memory cells,’” explains Letvin. “They then quietly ‘hang out’ in the background until another infection develops, and then these memory cells respond very quickly and forcefully [to ward off the new infection].”
Although evidence had existed that the gamma delta T cells provided protection against a range of infections, the immune responses of these cells had not been analyzed in detail. Chen and the study’s co-authors evaluated macaques that had previously been infected with BCG [bacteria closely related to the bacteria that causes tuberculosis] and reinoculated them with BCG. The animals were then assessed for T cell memory responses.
As early as four to six days after the second BCG inoculation, there was a marked expansion of the gamma delta T cells in the blood of the monkeys, which was two to nine times as great as the expansion during the primary infection. Furthermore, the authors found that the expansion of the cells lasted as long as seven months after the second BCG inoculation.
“This study, for the first time, shows that this population of gamma delta T cells straddles the boundaries between innate and more mature immunity,” explains Letvin. “Dr Chen's work has shown that these lymphocytes actually have the ability to develop memory. If you vaccinate a monkey with the tuberculosis vaccine, then subsequently infect it with the tuberculosis bacteria, the gamma delta T cell immunity develops very, very rapidly and is effective in controlling the tuberculosis infection. This suggests that the difference between innate and acquired immunity can't always be easily differentiated. Not only do these T cells have memory capabilities, but the monkeys are calling upon them to fight infection.
“This finding could change how we approach the development of a vaccine to fight tuberculosis,” he adds. “Our current vaccine is so marginally effective that it's not even used in the United States. We need to have a fully effective vaccine, and the implications of this study are important as we work toward that goal.”
Study co-authors include BIDMC researchers Yun Shen, M.D., Dejiang Zhou, M.D., Liyou Qiu, Xloamin Lai, M.D., Ling Shen, M.D., Zhongchen Kou, M.D., Qifan Wang, Liming Jiang, M.D., Yunyaun Li, M.D., and Xuejun Zeng, M.D.; Jim Estep, Ph.D., Robert Hunt, D.V.M., and Michelle Clagett of Battelle Memorial Institute, Columbus, Ohio; Prabhat K. Sehgal, D.V.M., of the New England Regional Primate Research Center; Craig T. Morita, M.D., Ph.D., of the University of Iowa; and Michael B. Brenner, M.D., of Brigham and Women's Hospital, Boston.
The study was funded by grants from the National Institutes of Health (NIH).
Beth Israel Deaconess Medical Center is a major patient care, research and teaching affiliate of Harvard Medical School and a founding member of CareGroup Healthcare System. Beth Israel Deaconess is the third largest recipient of National Institutes of Health research funding among independent U.S. teaching hospitals.
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Science