Immunofluoresence image of the marginal zone (see further reading)

Adhesion molecules have an important role in the localization of marginal-zone (MZ) B cells, according to a study published in the 19-July issue of Science. Lu and Cyster show that the integrins α4β1 and αLβ2 (also known as leukocyte function-associated antigen 1, LFA1) are essential for keeping MZ B cells in their place.

B cells in the splenic MZ — a structure that filters particulate antigens from the blood — are phenotypically and functionally distinct from B cells in the nearby follicles. But, the mechanisms that are responsible for the localization and segregation of MZ B cells have not been determined.

In this study, the expression of integrins on MZ and follicular B cells was compared; MZ B cells were found to express higher levels of the integrins α4β1 and αLβ2. Consistent with this, MZ B cells were shown to stick better than follicular B cells to the α4β1 ligand vascular cell-adhesion molecule 1 (VCAM1) and the αLβ2 ligand intercellular cell-adhesion molecule 1 (ICAM1). Immunohistochemical analysis of the spleen showed that ICAM1 and VCAM1 are indeed strongly expressed in the MZ.

To test the importance of α4β1–VCAM1 and αLβ2–ICAM1 interactions for the localization of MZ B cells in vivo, mice were treated with blocking antibodies specific for α4 and αL. Within three hours, there was a complete exodus of B cells from the MZ into the blood, but the B-cell follicles were unaffected, which confirms that these adhesive interactions have an essential role in the retention of B cells in the MZ.

B cells migrate into the follicles in response to the chemokine CXCL13 — how do MZ B cells resist this attraction? It seems that integrin interactions might be important, because follicular B cells were shown to migrate freely in response to CXCL13 on VCAM1-coated plates, whereas the migration of MZ B cells was inhibited.

Although MZ B cells do not recirculate, they migrate into the follicles in response to bacterial products and take antigens with them. Does integrin activity regulate this movement? Lipopolysaccharide (LPS)-treated MZ B cells had decreased adhesion to VCAM1 and were more responsive to CXCL13. When treated with LPS, the MZ B cells of Cxcl13−/− mice relocated to the blood, rather than to the B-cell follicles, which indicates that down-regulated integrin activity normally allows LPS-triggered MZ B cells to migrate to the follicles in response to CXCL13.

Importantly, these findings might explain the lack of MZ B cells in lymphotoxin α1β2 (Ltα1β2)−/−, Pyk2 −/− and Dok1 −/− mice — LTβR signalling seems to be required for the expression of ICAM1 and VCAM1 in the MZ, and PYK2 and DOK1 are known to be signalling components downstream of integrin signalling.