A team led by UCSF scientists has determined how the weapons producers of the immune system – the B cells that make antibodies – find the T cells they must team up with to attack invading pathogens. The discovery may provide a strategy to block autoimmune diseases, the study’s leaders suggest.
Chemical attraction is the key, the researchers found. Before they encounter foreign microbes, B cells concentrate in regions where few T cells reside, moored by their attraction to a certain kind of molecule called a chemokine. But contact with antigen from an invading microbe triggers changes in the B cell surface that draw them, irresistibly, to another type of chemokine, concentrated in T cell-rich sites.
This shifting balance of opposing chemical attractants may underlie a broad range of cellular movement in embryological development, the scientists conclude.
The research, based on studies of mice, is published in the March 7 issue of the journal Nature.
In their “naÃ¯ve” state, before they encounter antigen from potential pathogens, B cells cruise through the lymphatic system – principally the spleen and lymph nodes – seeking signs of foreign invaders. In this state, they are receptive to a type of chemical attractant, or chemokine called CXCL13, largely restricted to a neighborhood populated by other B cells and known simply as the “B zone”.
But when stimulated by an antigen signal from a foreign microbe, the B cell doubles the number of receptors on its surface cued to a different group of chemical attractants known as CCL19 and CCL21, the researchers found. This makes all the difference, since these attractants are found in far greater concentration where T cells reside -- the “T zone.” The increased receptiveness to these signals prompts the B cell to migrate within the lymphatic tissue from the B zone to the boundary between the B and T zones where cells of the two types can pair up. The pairing is known to be essential for the immune system to mount an antibody attack.
“We have known for some time that the antigen triggers a change that prompts B cell migration, but we didn’t know how the process worked,” said Jason Cyster, PhD, a Howard Hughes Medical Investigator and UCSF associate professor of microbiology and immunology. “This process is not only critical in the action of most vaccines, but it likely plays a central role in autoimmune diseases. Blocking these attractants may prove an effective strategy to block auto-antibody mediated disease. ” Cyster is senior author on the Nature paper.
In experiments with mice and mice cells, the researchers used a gene therapy approach to show that artificially increasing the numbers of receptors for T zone chemokines, CCL19 and CCL21, on B cells was sufficient to cause B cell migration to the T zone. Reciprocally, B cells with artificially increased receptors for the B zone chemokine, CXCL13, “overcame” the attractive signals from the T zone and headed back home to the B cell neighborhood.
Using B cells from mice with mutations in the receptor for the T zone chemokines, the researchers showed that this receptor was essential for the re-routing behavior. B cells with increased receptors for T zone chemokines (CCL19 and CCL21) but no receptors for the B zone chemokine CXCL13 no longer took the route that ran along the boundary of the two neighborhoods, but instead headed directly toward “T zone central.”
The findings led to the conclusion that B cell movement in response to the antigen is determined by the balance of responsiveness to the two kinds of chemical attractants made in adjacent zones – a kind of push-pull in which the B cells are much more responsive to being pulled toward the T zone after they are exposed to the antigen. While the mechanism is clear and convincing, other factors, such as adhesion molecules, may also play a role the researchers suggest.
Cell migration is critical not only in the adult immune defense, but in all phases of embryonic development when, for example, neurons must find their way to their targets and muscle cells must interact and fuse. The role of chemokines or other chemical attractants uncovered in this study, creating zones that draw cells in depending on subtle changes in the amount of receptors arrayed on the cell’s surface, may be a general pattern found widely in development, Cyster suggests.
The researchers now hope to determine whether similar changes in chemokine receptor levels are involved in redirecting the movement of autoreactive B cells. If this proves to be true, they think they may be on the path to resolving what goes wrong in some people to cause auto-antibody-mediated disease. Understanding this malady at the molecular level has been a long standing problem in immune system research.
Co-first authors on the Nature paper are Karin Reif, PhD, postdoctoral scientist, and Eric H. Ekland, BS, an HHMI predoctoral fellow, both in microbiology and immunology at UCSF.
Collaborators on the research and co-authors are Lars Ohl, PhD, a postdoctoral scientist at Nikolaus-Fiebiger Center, Erlangen, Germany; Hideki Nakano, PhD, a postdoctoral researcher at Duke University; Martin Lipp, PhD, a professor in immunology at the Max Delbruck Center for Molecular Medicine, Berlin, Germany; and Reinhold Forster, PhD, a professor of immunology at the Nikolaus-Fiebiger Center.
The research was supported in part by the National Institutes of Health.
Editors Note: A diagram and caption describing the newly discovered immune system process can be accessed at: pub.ucsf.edu/