Mobilizing front-line immune defenses

05 January 2007 (Volume 2 Issue 2)

New data highlight ways in which immune cells are quickly pulled into the fight against microbial intruders

Figure 1: An image of omentum, the exit route from the peritoneal cavity, with B1 cells (red) and blood vessels (green).

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Researchers report fresh insight into the events required for rapid recruitment of immune cells, called B1 lymphocytes, to lymphoid organs. In quiescent conditions, B1 lymphocytes reside between the membranes lining the abdominal cavity—the peritoneum. Post-infection, these immune cells are among the first to arrive in lymphoid organs, where later phases of the immune response develop. Due to their exquisite sensitivity to the presence of immune ‘danger signals’, B1 lymphocytes constitute ideal first responders.

Now a research team led by Sidonia Fagarasan, a scientist at RIKEN’s Research Center for Allergy and Immunology in Yokohama, has determined precisely how B1 cells sitting within the peritoneum quickly traffic towards immune responses developing at distant locales throughout the body¹.

To simulate conditions of an infection, the team injected mice with a drug that injures the gut epithelium, thereby allowing microbes normally present within the small intestine to penetrate tissues close to the peritoneum. Dramatically, within six hours of drug injection, a substantial portion of B1 cells proceeded from the peritoneum to the spleen and gut-associated lymphoid organs (Fig.1).

The researchers hypothesized that proteins decorating the surface of bacteria might somehow provoke B1 cells to leave the peritoneum. Indeed, B1 cells departed the peritoneum after injection of lipid A, a component of many types of bacteria. In contrast, B1 cells lacking the sensor required for recognition of lipid A, known as Toll-like receptor 4, remained in the peritoneum even after lipid A injection.

The team also revealed the underlying mechanism. B1 lymphocytes express high amounts of proteins that allow cells to adhere or stick to tissues. However, exposure to lipid A triggered a drop in the expression of two such adhesion proteins known as integrins and CD9. Blockade of these adhesion proteins, even in the absence of bacterial components, allowed B1 cells to ‘disengage’ and leave the peritoneum.

However, B1 cell egress from the peritoneum was not the result of passive drift alone. After injection of bacterial components, cells lining the B1 cell departure route ramped up production of soluble proteins called chemokines, which actively attract B1 cells. Accordingly, B1 cells unable to receive chemokine signals remained within the peritoneum.

Unraveling the complexity of the series of events required to disengage B1 cells from the peritoneum presents multiple opportunities for therapeutic intervention. “These findings will open a new phase in immunology and hopefully in cancer research, because adhesion proteins on tumor cells may be regulated by similar mechanisms,” says Fagarasan.

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1. Ha S.A., Tsuji, M., Suzuki, K., Meed, B., Yasuda, N., Kaisho, T. & Fagarasan S. Regulation of B1 cell migration by signals through Toll-like receptors. The Journal of Experimental Medicine 203, 2541–2550 (2006). | article |