‘Class equals function’ in Scripps immunology study

Scripps Research Institute scientists show how memory B cells stay 'in class' to fight different infections, and these new observations about the internal programming of B cells could influence the development of more efficient vaccines for a host of infections and even some autoimmune diseases

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LA JOLLA, Calif.—In a recent Nature Immunology paper, scientists from the Scripps ResearchInstitute detail groundbreaking observations about the internal programming ofB cells, the immune cells that make antibodies against infections. According tothe Scripps team, their findings could influence the development of moreefficient 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 howits antibodies marshal other components of immunity, and thus how well they canremove a certain type of threat, such as bacteria on the skin or intestinalparasites.
"Our findings could usher in a way to rationally designvaccines and shape adaptive immune response," says Michael McHeyzer-Williams,the principal investigator for the study. "This is the first study thatblatantly states that B cell memory is organized into different pathways thatneed to be examined across different isotypes. Until now, we haven't really hada good conceptual framework for the development and maintenance of thesecells."
McHeyzer-Williams' work with B cells began even before heearned 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 researchfocuses on regulating adaptive immunity, of which helper T cells are the masterregulators and control the development of antigen-specific B cell immunity.
"Our research seeks to define the cellular and moleculardetails of the major developmental checkpoints that regulate these cell fatedecisions in vivo," he says. "We haverecently extended our studies into the earliest innate immune events thatinitiate and shape this adaptive immune response. If we can understand therules that control adaptive immunity, it will be possible to design safe andeffective protein subunit vaccines."
In particular, McHeyzer-Williams is concerned withunderstanding how B cell memory is organized and how this knowledge can be usedto initiate certain immune responses. Antibody class defines function in B cellimmunity, but how class is propagated into B cell memory remains poorlyunderstood. 
According to the Scripps team, memory B cells are long-livedantigen-experienced B cells that typically express a high-affinity B cellantigen receptor (BCR), rapidly expand their populations and differentiate intoplasma cells after antigen rechallenge. Although memory B cells that expressimmunoglobulin M (IgM) have specialized functions, many antigen-primed B cellsswitch to non-IgM isotypes under the antigen-specific regulation of follicularhelper T cells. Furthermore, non-IgM classes of membrane-bound antibody havedifferent abilities to transduce signals through their BCR on the basis of theconstant region expressed.
The class of a B cell is marked by the type of "stem" it hason its Y-shaped antibodies; this stem, or effector, can mobilize other elementsof the immune system, such as inflammatory chemicals, when the antibody bindsto an invader. IgG-class B cells are the most common in humans, and are broadlyeffective against viruses and bacteria. IgA-class B cells are predominantlyfound on mucosal surfaces such as in the throat and intestines. IgE-class cellsand their antibodies protect against intestinal worms and other parasites. SomeB cells stay in the default IgM class.
However, little is known about the molecular signalsrequired for the survival, activation or differentiation of class-switchedmemory B cells, notes McHeyzer-Williams.
"The notion of class has always been there, but it hasn'treceived a lot of attention in the last 10 years or so," he says. "We startedfrom the idea that it is reasonable to hypothesize that memory is sorted byclass, because class equals function."
The team also started from the idea that when T cells causenaïve B cells to switch to the IgG2a class, a potent antiviral class, they doso 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 Bcells lack the protein.
McHeyzer-Williams and his colleagues observed that withoutT-bet, the mouse B cells could not be switched to the IgG2a class, even whenpresented with all the normal stimuli, and even though other IgG classes couldbe produced normally—or even in higher amounts.
"All of the data kept fitting that same principle," theprofessor 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 torespond to a new infection. In fact, most of the T-bet-deprived memory B cellsbecame undetectable within a few days.
The finding that T-bet has this all-important, ongoingfunction in IgG2a memory cells suggested that other proteins play analogousroles in other classes of memory B cell. The scientists then turned to memory Bcells of the IgA class, and with a similar set of experiments, showed thatthese memory B cells depend on the transcription factor RORα.
The Scripps team is now searching for the proteins that keepother memory B cells healthy and in their classes. Their hope is that bysupplying a particular class-enforcement protein at the same time that itexposes B cells to microbial proteins, a vaccine could induce a long-termimmunity 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," saidMcHeyzer-Williams. "So the goal would be to design a chemical adjuvant for thevaccine that drives B cells into those classes."
In addition, therapies that knock down class-enforcementsignals such as T-bet could usefully reduce or eliminate memory B cells incertain classes.
"Some autoimmune, allergic and lymphoma conditions aredriven 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 wouldbe an obvious advantage over existing therapies, such as steroids, that knockdown large parts of the immune system.
"These types of findings bring fundamental immunology intothe world of vaccinology," he concludes. "This makes the era of preventivemedicine and personalized medicine much more tangible."
The study, "Divergent transcriptional programming ofclass-specific B cell memory by T-bet and RORα," was published May 6 in the onlineversion of Nature Immunology. Othercontributors to the paper were Nathaniel Wang, a CTSA TL-1 scholar inassociation 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 crucialreagents for manipulating RORα levels; and Steven L. Reiner of ColumbiaUniversity's College of Physicians and Surgeons, who supplied transgenic mice.The research was funded in part by the U.S. National Institutes of Health.

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