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‘Class equals function’ in Scripps immunology study
LA JOLLA, Calif.—In a recent Nature Immunology paper, scientists from the Scripps Research Institute detail groundbreaking observations about the internal programming of B cells, the immune cells that make antibodies against infections. According to the Scripps team, their findings could influence the development of more efficient vaccines for a host of infections and even some autoimmune diseases.
In the paper, the scientists show how memory B cells stay "in class" to fight different infections. The class of a B cell determines how its antibodies marshal other components of immunity, and thus how well they can remove a certain type of threat, such as bacteria on the skin or intestinal parasites.
"Our findings could usher in a way to rationally design vaccines and shape adaptive immune response," says Michael McHeyzer-Williams, the principal investigator for the study. "This is the first study that blatantly states that B cell memory is organized into different pathways that need to be examined across different isotypes. Until now, we haven't really had a good conceptual framework for the development and maintenance of these cells."
McHeyzer-Williams' work with B cells began even before he earned his Ph.D. in immunology in 1991 from the University of Melbourne in Australia. Now a professor of immunology at the Scripps Research Institute, his research focuses on regulating adaptive immunity, of which helper T cells are the master regulators and control the development of antigen-specific B cell immunity.
"Our research seeks to define the cellular and molecular details of the major developmental checkpoints that regulate these cell fate decisions in vivo," he says. "We have recently extended our studies into the earliest innate immune events that initiate and shape this adaptive immune response. If we can understand the rules that control adaptive immunity, it will be possible to design safe and effective protein subunit vaccines."
In particular, McHeyzer-Williams is concerned with understanding how B cell memory is organized and how this knowledge can be used to initiate certain immune responses. Antibody class defines function in B cell immunity, but how class is propagated into B cell memory remains poorly understood.
According to the Scripps team, memory B cells are long-lived antigen-experienced B cells that typically express a high-affinity B cell antigen receptor (BCR), rapidly expand their populations and differentiate into plasma cells after antigen rechallenge. Although memory B cells that express immunoglobulin M (IgM) have specialized functions, many antigen-primed B cells switch to non-IgM isotypes under the antigen-specific regulation of follicular helper T cells. Furthermore, non-IgM classes of membrane-bound antibody have different abilities to transduce signals through their BCR on the basis of the constant region expressed.
The class of a B cell is marked by the type of "stem" it has on its Y-shaped antibodies; this stem, or effector, can mobilize other elements of the immune system, such as inflammatory chemicals, when the antibody binds to an invader. IgG-class B cells are the most common in humans, and are broadly effective against viruses and bacteria. IgA-class B cells are predominantly found on mucosal surfaces such as in the throat and intestines. IgE-class cells and their antibodies protect against intestinal worms and other parasites. Some B cells stay in the default IgM class.
However, little is known about the molecular signals required for the survival, activation or differentiation of class-switched memory B cells, notes McHeyzer-Williams.
"The notion of class has always been there, but it hasn 't received a lot of attention in the last 10 years or so," he says. "We started from the idea that it is reasonable to hypothesize that memory is sorted by class, because class equals function."
The team also started from the idea that when T cells cause naïve B cells to switch to the IgG2a class, a potent antiviral class, they do so by inducing the production in B cells of a particular protein called T-bet. To clarify T-bet's role, the researchers engineered transgenic mice whose B cells lack the protein.
McHeyzer-Williams and his colleagues observed that without T-bet, the mouse B cells could not be switched to the IgG2a class, even when presented with all the normal stimuli, and even though other IgG classes could be produced normally—or even in higher amounts.
"All of the data kept fitting that same principle," the professor adds, and even more surprisingly, in existing IgG2a memory B cells, the abrupt knockdown of T-bet levels caused the cells to lose their ability to respond to a new infection. In fact, most of the T-bet-deprived memory B cells became undetectable within a few days.
The finding that T-bet has this all-important, ongoing function in IgG2a memory cells suggested that other proteins play analogous roles in other classes of memory B cell. The scientists then turned to memory B cells of the IgA class, and with a similar set of experiments, showed that these memory B cells depend on the transcription factor RORα.
The Scripps team is now searching for the proteins that keep other memory B cells healthy and in their classes. Their hope is that by supplying a particular class-enforcement protein at the same time that it exposes B cells to microbial proteins, a vaccine could induce a long-term immunity that is heavily weighted towards a desired antibody class.
"If you're designing a vaccine for certain types of virus, for example, you would like to have lots of IgG2a and IgA memory cells," said McHeyzer-Williams. "So the goal would be to design a chemical adjuvant for the vaccine that drives B cells into those classes."
In addition, therapies that knock down class-enforcement signals such as T-bet could usefully reduce or eliminate memory B cells in certain classes.
"Some autoimmune, allergic and lymphoma conditions are driven by B cells of a particular class, for example IgE cells in allergies," said McHeyzer- Williams. "Being able to target just that class of B cell would be an obvious advantage over existing therapies, such as steroids, that knock down large parts of the immune system.
"These types of findings bring fundamental immunology into the world of vaccinology," he concludes. "This makes the era of preventive medicine and personalized medicine much more tangible."
The study, "Divergent transcriptional programming of class-specific B cell memory by T-bet and RORα," was published May 6 in the online version of Nature Immunology. Other contributors to the paper were Nathaniel Wang, a CTSA TL-1 scholar in association with the Scripps Translational Science Institute; Louise J. McHeyzer-Williams and Shinji L. Okitsu of the McHeyzer-Williams lab; Thomas P. Burris of the Jupiter, Fla. campus of Scripps Research, who provided crucial reagents for manipulating RORα levels; and Steven L. Reiner of Columbia University's College of Physicians and Surgeons, who supplied transgenic mice. The research was funded in part by the U.S. National Institutes of Health.