Specialized Immune-System B Cells Play Double-Barreled Role
DURHAM, N.C. -- A specialized subpopulation of the antibody-producing B cells of the immune system plays a "double-barreled" role in triggering both kinds of immunity -- innate and acquired, Duke University Medical Center immunologists have discovered. The division of labor between B-1a and B-1b cells they have uncovered offers basic insights that could contribute to more rational development of vaccines, they said.
B cells are the arms factories of the immune system, producing antibodies that target invading microbes for destruction. Generally, B-1 cells have been thought to play a major role in the innate immune response -- the type of immunity that offers rapid, generalized responses to infections. Less understood has been any role in adaptive immunity -- in which the immune system develops a long-term immune response to an invader after vaccination or infection.
The researchers -- Karen Haas, Jonathan Poe, Douglas Steeber and Thomas Tedder -- published their findings in the July 2005 issue of the journal Immunity. The research was sponsored by the National Institutes of Health, the Arthritis Foundation, the Lymphoma Research Foundation and the Leukemia & Lymphoma Society.
The researchers studied a particular type of B cell called the B-1 cell. In contrast to the more conventional B-2 cells, B-1 cells have different distinguishing characteristics such as behavior, anatomical localization and types of antibodies produced. In contrast to well-studied B-2 cells, the cellular origins of B-1 cells and their subtypes remain unknown.
"The true function of B-1 cells in the body has been highly controversial over the past two decades," said Tedder. "They appear to be a primary defense mechanism for innate immunity in infections. In particular, however, the B-1b cells have been largely ignored because they're present in relatively small numbers and are difficult to work with."
In the studies, Haas and her colleagues used two genetically altered mouse strains -- one that overproduced and one that was deficient in a protein called CD19 that is a key regulator of B-1a cell function and development. Thus, the two mouse strains enabled the researchers to explore the consequences of too many or too few B-1a cells. Also, the strain lacking CD19, and therefore B-1a cells, enabled the researchers to isolate sufficient numbers of pure B-1b cells for study.
The researchers studied how the immune systems of the two mouse strains reacted to infection with Streptococcus pneumoniae, the bacterium that causes pneumonia. They found that the mice lacking B-1a cells were susceptible to infection, showing they lacked the natural antibodies of the innate immune system. Yet, these mice could be protected by immunization, which activated their adaptive long-term immune system.
By contrast, the mice with overproduction of CD19 and thus overproduction of B-1a cells did not achieve adaptive immunity as a result of vaccination.
Thus, the researchers concluded that the B-1a cells regulate the innate immune response and the B-1b cells regulate the adaptive, long-term immune response.
Said Haas, "This reciprocal contribution of these two subtypes of B-1 cells to innate and acquired immunity was surprising to us. No one knew much about what these subsets do. Our results indicate that there is a tiered response system in which one kind of B-1 cell consistently provides a low level of protection, while the other specifically responds to an infection to help eliminate it."
According to Haas and Tedder, the findings offer potential insights into the mechanism of vaccine action. For example, the new insights into the roles of the two B-1 cell subtypes could help explain why the immune-triggering molecules called antigens from the pneumococcus bacteria do not elicit a strong adaptive immune response in infants, people with compromised immune systems and the elderly. Such people may not have developed sufficient populations of B-1b cells to mount such an adaptive response.
According to Tedder, such basic insights as the new study yielded could be important for rational design of vaccines.
"Most vaccines are designed simply empirically," he said. "The designers develop a formulation that's a best guess and test it on patients or animal models to determine its effectiveness. But now, research is reaching a point where we can understand the signals that switch certain B cell populations on and off and regulate their function.
"We certainly cannot say whether these particular findings about the role of these B-1 cell subtypes will directly impact on vaccine development," said Tedder. "However, understanding such key characteristics of the immune regulatory process will be critical to learning to successfully manipulate it with vaccines."