Fran Lund, Ph.D., professor in the UAB Department of Microbiology and director of the UAB Immunology Institute, along with other UAB researchers, recently published a study in Immunity illustrating the crucial role a protein called T-bet plays in protecting the body’s immune response to influenza.
Here, Lund gives insights into the research, “Transcription factor T-bet regulates the maintenance and differentiation potential of lymph node and lung effector memory B cell subsets.”
Q: What inspired you to conduct this study?
Lund: We previously identified a new population of memory B cells in humans. We showed that these human “effector” memory B cells express the transcription factor T-bet and demonstrated that effector human memory B cells could quickly transition into plasma cells that produce antibodies that we know are important for protection from infection. While these studies showed that T-bet could be used to identify human memory B cells with the potential to rapidly respond to infection, it was not possible to address in humans whether T-bet was simply a marker for these cells or whether T-bet was also required for the development, maintenance, or localization of these memory B cells. In addition, we could not prove in humans that these effector memory B cells can protect people from developing more severe infections following exposure to influenza virus.
Q: What were your goals for the study?
Lund: The goal was to use mouse models of influenza infection to ask three questions. The first question was whether T-bet could also be used to identify mouse memory B cells that have the capability to rapidly become antibody-secreting cells. If this were true, then we planned to address whether T-bet expression by these memory B cells was important for these cells and whether these T-bet-expressing memory B cells did, in fact, provide immune protection.
Q: What did the results of the study show?
Lund: We found that a subset of the mouse flu-specific memory B cells express T-bet and that the T-bet-expressing memory B cells, but not the other memory B cells, had the properties of effector cells and rapidly produced antibody after reactivation. Thus, this population of memory B cells is seen in both mice and humans. Using the mouse model where we can remove genes of interest, we showed that T-bet, while not required for the development of effector memory B cells, was required for the maintenance and function of these cells in lymph nodes and in the flu-infected lung. Finally, we showed that following re-infection with influenza virus, T-bet-expressing lung memory B cells are important for the early antibody response at the site of infection. Therefore, T-bet is not only a biomarker for effector memory B cells but is also important for the maintenance and function of the memory B cells that are known to decrease severe disease following infection.
Q: How do you hope these results will positively impact clinicians/patients?
Lund: These are very basic science studies that help us to understand what signals are needed to elicit and maintain protective immune cells. Our data suggests that what we learned in mice may also be applicable to humans as we were able to identify very similar populations of T-bet expressing memory B cells in both species. In mice, we showed a role for T-bet in the maintenance and function of the effector memory B cells, and we also showed what signals are required to induce expression of T-bet in these memory B cells. Therefore, we can now ask whether those same signals will elicit the T-bet memory B cells in humans. If so, in the future, we might be able to specifically turn those B cells on during infection or cancer and potentially turn those B cells off in other settings like autoimmunity and transplantation, where we want to suppress the formation and maintenance of potentially pathogenic effector memory B cells.
Q: What are your future goals as it relates to these results?
Lund: One of our future goals is to see whether we can suppress T-bet-expressing effector memory B cells in animal models of autoimmunity and transplantation. If so, then we can consider how to develop therapeutics that might eliminate these cells in settings where the B cells cause or contribute to disease.
Q: Is there anything else you’d like to add?
Lund: Studying human immune responses is critical to understanding what cells participate in the response; however, it’s hard to understand how the immune cells were activated in humans, particularly when most immune cells do not stay in the blood but actually live long-term in tissues like the lung. Although animal models can never recapitulate everything about human immune responses, the animal models can be used to mechanistically evaluate immune cell populations. What we learn from those studies often allows us to go back and ask more targeted, but still very basic, questions in humans. In our lab, we often start with interrogating the human immune system, then use appropriate animal models to define the molecular regulators of the animal response, and then return to human patients to see whether we can use the mechanistic information to manipulate the human immune cells in the settings of disease.