The body has an intricate system to defend against infections where each type of immune cell plays a distinct role. Now, a study led by researchers from the Penn State College of Medicine has uncovered a new function of the immune cells that are known for making antibodies. They determined that, in response to flu infection, a specialized set of B cells produce a key signaling molecule that the immune system needs to develop a robust, long-term response to fight off infections.
It's a function that has not previously been seen in these types of cells. The finding highlights a potential target for improving immunizations, particularly the flu vaccine, and future therapies for conditions like cancer and autoimmune disease. The team published their study in PLOS Pathogens.
"It's paradigm-shifting. The pathway for producing the cytokine called interleukin-1 beta - a messenger that helps coordinate immune response - has almost exclusively been seen in the body's front-line, innate immune cells. Yet here, we see it in B cells in a specialized area of the lymph node called the germinal center, which is part of the body's adaptive immune response. We don't expect them to do that," said S. Rameeza Allie, assistant professor of microbiology and immunology at the Penn State College of Medicine and senior author on the paper.
When a pathogen like the flu virus enters the body, it sets off a cascade of responses, the research team explained. First, the body's front-line defense, called innate immunity, jumps into action to battle the pathogen and broadly suppress the infection. At the same time, the body gathers information about the pathogen and develops a targeted response using B cells and T cells, two types of white blood cells. This adaptive immunity, while slower to develop, is crucial for survival because it remembers pathogens and provides long-lasting protection. If the immune system encounters the same pathogen again, it mounts a faster, more robust response and protects against re-infection.
Germinal centers are key to developing good adaptive immunity, the researchers explained. These are areas that form in the lymph nodes in response to an infection or immunization and act as a training ground for B cells. Germinal center B cells, or GC B cells, multiply and undergo rapid changes to produce highly specific antibodies and memory B cells.
"The focus of our lab is understanding how we make this germinal center work better so that we can have these very protective memory B cells," Allie said. "Studies have shown that if you can make the germinal centers persist longer, the production of memory B cells is really good."
Allie explained that the interleukin-1 beta is necessary for a high-quality germinal center. Germinal centers need T follicular helper (TFH) cells in order to persist, and these TFH cells, in turn, need interleukin-1 beta to function. Without interleukin-1 beta, there are fewer TFH cells and germinal centers are smaller in size.
This study demonstrated that GC B cells produce interleukin-1 beta locally in the germinal center, and supplies it to TFH cells, a relationship that was previously unknown, the researchers said. The findings highlight the two-way relationship between these immune cells and how they work together to promote better quality germinal centers.
"We've known about B cells for a long time, and we know that their prominent function is to produce antibodies. But here, we show that they aren't just antibody-producing cells. They are also helper cells for other immune cells and are essential for TFH cells to do their job and therefore the germinal center, too," said Juliana Restrepo Munera, doctoral candidate in cell and biological systems at the Penn State College of Medicine and first author of the study.
The research team validated their data in a mouse model of influenza and in human B cells. They found that GC B cells produce interleukin-1 beta through a well-studied mechanism which uses a multi-protein complex called the NLRP3 inflammasome. When activated, this protein complex triggers the release of cytokines like interleukin-1 beta. Prior to this work, this inflammasome wasn't widely linked to adaptive immunity. The researchers found that the inflammasome and interleukin-1 beta were expressed by GC B cells but not by other B cells. Without the inflammasome or interleukin-1 beta, TFH cells didn't function effectively and the germinal centers weren't well formed.
This finding could point to ways to enhance the response and prolong the activity in the germinal center by targeting the NLRP3 inflammasome pathway or GC B cell-derived interleukin-1 beta, Restrepo Munera explained. It could inform future flu vaccine strategies to provide better protection against viruses that constantly evolve. It could also lead to better ways to manage immune response in conditions like autoimmune disease and cancer.
"There's so much translational potential because this is a cytokine that's been studied and has been used in clinical settings," Allie said.
The research team said they plan to continue this line of research to understand what's required for the formation of optimal germinal centers and how to enhance their interaction between the GC B cells and TFH cells.
Funding from the Penn State College of Medicine supported this work.
