Immunology: Curious About B-Cell Activation
When Hai Qi, M.D., Ph.D., was a graduate student at the University of Texas Medical Branch in Galveston several years ago, he worked on a group of tropical parasites called Leishmania. The specific pathogen Dr. Qi had been studying was a curious Leishmania species because when it infected mice, the rodents would fare better if their immune systems were suppressed. But why?
Dr. Qi tried to explain this phenomenon by examining how the parasite might exploit dendritic cells, which act as a master regulator of the immune system. He was aware, however, that B cells, another important component of the immune system, might also play a role. B cells produce antibodies, which usually fight infections, but in this case, antibodies produced by certain B cells in the infected mice directly help the parasite spread.
Dr. Qi wondered whether dendritic cells and B cells are somehow connected in the immune response to Leishmania infection. One day, he determined that Leishmania-infected dendritic cells display specific pieces of the parasite (known as antigens) on their surfaces. He realized that this could mean the dendritic cells were playing a previously unforeseen role in activating the B cells. But how could he prove it?
A moment of curiosity like this might come and go, but with Dr. Qi, it stuck. It prompted him to study B cell activation, and this interest led him to the laboratory of National Institute of Allergy and Infectious Diseases (NIAID) intramural scientist Ron Germain, M.D., Ph.D., an internationally renowned immunologist, where Dr. Qi now works as a postdoctoral research fellow. Their work together bore fruit in a report published in the journal Science last year.
Using a powerful microscope and fluorescent tags to track the movement and behavior of B cells, they captured images of B cells being activated by dendritic cells in a live mouse. B cells are usually activated when they recognize a specific antigen, signaling the presence of a microbe or other foreign substance. Once activated, B cells multiply and begin producing antibodies that help clear the body of infection.
The body tightly controls the activation of B cells to prevent an overactive immune response that could damage healthy tissues. For B cells to become activated, for example, they must recognize specific antigens and receive a boost from an already activated “helper” T cell that recognizes the same antigen. Helper T cells themselves cannot be activated unless they encounter a specific antigen on the surface of a third type of immune cell—usually an activated dendritic cell.
The immune system increases the chances of this specific B cell–T cell interaction happening by concentrating immune cells in the lymph nodes—immune organs that filter tissue fluids for viruses, bacteria, and other microbes. In the lymph nodes, circulating immune cells can detect antigen from these microbes and become activated. Often, dendritic cells are the vehicles that bring microbial antigen from the tissues to the lymph nodes.
Real-time Imaging of B Cells in Deep Tissues
B cells entering lymph nodes from the bloodstream generally collect in specialized areas known as follicles. Scientists had long thought that B cells recognize antigen in the follicles, exit the follicles, and only then become activated if they encounter activated helper T cells.
One problem with this theory, say Drs. Qi and Germain, has been that some pieces of antigen are too big to enter the follicles. Now their work suggests the antigen may not have to.
Using a specialized microscopic method that allows real-time imaging of immune cells in deep tissues of living mice, they tracked the behaviors of fluorescently tagged dendritic cells and B cells in the lymph nodes. They employed a trick that makes B cells light up in a distinct color when they detect antigens—something not previously done in a living mouse—which helped them spot exactly when and where those B cells were being activated.
They observed B cells entering the lymph nodes and becoming activated after interacting with dendritic cells bearing the correct antigens. All this happened before the B cells could enter the follicles.
What the microscopic videos show, says Dr. Qi, is that besides their more familiar role in activating helper T cells, dendritic cells carrying antigen to the lymph nodes can present their antigen to B cells and activate them. Drs. Qi and Germain think that this may be an important solution for how our B cells could produce antibodies to big pieces of antigens. Furthermore, by presenting antigen to B cells and helper T cells at the same time in nearby locations, dendritic cells may also serve to foster meetings of T cells and B cells that recognize the same antigen. To scientists like Drs. Qi and Germain, this is a novel aspect of dendritic cell biology that may one day open up new ways of boosting antibody responses.
Reference
Qi, H. et al. Extrafollicular activation of lymph node B cells by antigen-bearing dendritic cells. Science DOI: 10.1126/science.1125703 (2006).
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