More than 10 million people fall ill each year with tuberculosis in the world, which causes 1.5 million deaths. However, up to 2 billion people are infected with Mycobaterium tuberculosis, the bacterium that causes tuberculosis, and are otherwise healthy and asymptomatic. Scientists who study tuberculosis look to those individuals who can tolerate and contain the infection in the hope of developing better treatments and vaccines.
The key feature of tuberculosis infection in humans is the formation of granulomas, or clumps of immune cells in the lungs that contain the infection. These granulomas contain B cells, polyvalent immune cells that perform a variety of functions, from producing antibodies to regulating the activity of other cells. For years, researchers assumed that these B cells must be performing a specific direct function in granulomas to control tuberculosis infection, but in a new study, scientists from the University of Chicago and Washington University in St. Louis show that these B cells they are actually directing reinforcements to help.
In the study, published in “Nature Immunology,” the team eliminated one by one different expected functions of B cells in animal models of tuberculosis to narrow down the possibilities of which components prevented the progression of the disease. Nothing seemed to make a difference, whether the plasma cells that produce antibodies were eliminated or other functions of the B cells that produce immune signaling molecules were suppressed.
“It didn’t matter what we individually removed in the B cells, there was no difference. All the predicted jobs that people think B cells do were not the ones they do in the lung to protect against tuberculosis,” says Shabaana Khader, MD, Bernard and Betty Roizman Professor of Microbiology at UChicago and lead author of the study. . “But they had to be there, because when we completely knocked out the tuberculosis-specific B cells, the mice started to get sick. So we knew it wasn’t any of the usual suspects.”
In addition to the results in mice, the team observed the same results when they completely eliminated B cells in non-human primate models.
B cells are not the only immune cells present in granuloma tissue. T cells, another important white blood cell of the immune system, also play a role, specifically CD4+ or “helper” T cells, which can initiate immune responses. Both B and T cells interact to control the progression of TB, but until this study it was not entirely clear to what extent they contributed and interacted with each other.
Instead of directly controlling TB, B cells point Tfh cells in the right direction to do their job
When Khader and his team narrowed down the possible functions of B cells, they found that helper T cells express transcription factors that in turn generate subtypes of T cells, including follicular helper (Tfh) T cells that are localized to the tissue of the B cell. granuloma. It is these Tfh cells that activate the macrophages to keep the TB infection in check by surrounding and killing the infected cells, but the B cells tell them where to go and localize themselves inside the granulomas. So instead of directly controlling TB, B cells point Tfh cells in the right direction to do their job.
“An effective way to activate macrophages is to have Tfh-like cells go there and activate them, and that’s what B cells do,” Khader explains.
The only TB vaccine was first produced in 1921, and while it is effective in preventing some forms of childhood TB, its protection is highly variable in adults. Understanding how some people are able to control TB infection naturally could help develop better versions in the future.
“If the protective immune response can be initiated much earlier, the bacteria will never have a chance to establish infection in the lung,” explains Khader. “We could fdevelop a vaccine that elicits the right type of response so that when you are exposed to the bacteria, you are not even a carrier of the latent infection. So our resolution for vaccine design is much cleaner now, as we know which cell types to target in the lung.”