Two Billion People Carry Tuberculosis, But How Do They Keep It in Check? New Study Reveals
Globally, more than 10 million people get tuberculosis (TB) every year, and 1.5 million of them die as a result. Yet, it is estimated that as many as two billion individuals are asymptomatic carriers of the TB-causing Mycobaterium tuberculosis bacteria.
In order to create more effective therapies and vaccinations, TB researchers analyze people who have managed to live with the virus.
The primary characteristic of tuberculosis infection in humans is the development of granulomas – groups of immune cells in the lungs that confine the infection. These granulomas consist of B cells – versatile immune cells that carry out various functions, such as producing antibodies and regulating the activities of other cells. Researchers had long presumed that B cells played a specific role in controlling TB infection directly within the granulomas. However, a new study by the University of Chicago and Washington University in St. Louis reveals that B cells serve as guides to direct reinforcements to the site.
Published in Nature Immunology, the study involved progressively eliminating the various functions of B cells one by one in animal models of TB to identify which components impeded the disease’s progression. However, none of the interventions seemed to affect the outcome, regardless of whether they removed plasma cells that produce antibodies or other B cell functions that produce immune signaling molecules.
“No matter what we knocked out individually in B cells,” explains senior author Shabaana Khader, “it didn’t make a difference.”
The anticipated functions that were attributed to B cells in safeguarding the lungs against TB turned out to be incorrect.
“But they needed to be there, because when we knocked TB-specific B cells out completely, you start seeing that the mice get sick. So, we knew that it wasn’t any of these usual suspects.”
Apart from the findings in mice, the team obtained identical outcomes by entirely removing B cells in non-human primates models. While B cells are integral to granuloma tissue, T cells – another essential white blood cell of the immune system – also have a role to play, especially CD4+ or “helper” T cells that initiate immune responses. The interplay between both B and T cells is essential in containing tuberculosis, but the degree of their contributions and interactions was unclear until this study.
Dr. Khader and her team progressively narrowed down the potential functions of B cells and discovered that the helper T cells expressed transcription factors that produced T cell subtypes, such as T follicular helper (Tfh)-like cells that reside within the granuloma tissue. It is these Tfh-like cells that activate macrophages to suppress TB infection by enveloping and destroying infected cells. However, it is the B cells that direct them to the appropriate location within the granulomas. Instead of directly controlling TB, B cells serve as guides, directing Tfh-like cells towards the site where they can perform their function.
“An effective way to activate macrophages is to get Tfh-like cells to come there and activate them, and that’s what the B cell is doing,” Khader remarks.
The first tuberculosis vaccine was developed in 1921, and although it is helpful in avoiding certain kinds of pediatric TB, its protection for adults varies greatly. Knowing how some individuals are able to naturally regulate TB infection might aid in the future development of more effective treatments.
“If you can initiate the protective immune response much earlier, the bacteria will never get a chance to establish infection in the lung,” Khader adds. “We could make a vaccine that generates the right kind of immune response so that when you get exposed to the bacteria, you won’t even carry the latent infection. So, our resolution for vaccine design is much cleaner now since we know what cell types to target in the lung.”
Source: 10.1038/s41590-023-01476-3
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