Functional organization of secondary lymphoid organs by the chemokine system.

Abstract

The development of an adaptive immune response requires well coordinated mechanisms in order to navigate circulating immune cells through peripheral tissues and into secondary lymphoid organs. There is strong experimental evidence that chemokines and their receptors are responsible for recruiting cells involved in inflammatory processes as well as for homeostatic control of leukocyte traffic and functional compartmentalization of lymphoid organs. Functional interactions of chemokines with their receptors, which belong to the family of seven-transmembrane-domain proteins signaling through heterotrimeric G proteins, have been shown to be primarily implicated in pathophysiological inflammatory processes (reviewed in Rollins, 1997). Leukocytes are recruited from the blood by locally produced chemokines towards sites of inflammation arising from infections, injury, allergic reactions, arthritis and arteriosclerosis. Several lines of recent evidence suggest that members of the chemokine receptor family are also involved in lymphocyte migration to distinct lymphoid organs and control lymphocyte homeostasis (reviewed in Baggiolini, 1998). Mature B and T lymphocytes continuously recirculate between blood and lymphatics to mediate immune surveillance. In this process they have to interact and to pass specialized endothelia: postcapillary venules in non-lymphoid organs and high endothelial venules (HEVs) in lymph nodes. The recent finding that the chemokine receptor BLR1/CXCR5 is needed for B cell migration into lymphoid follicles (Förster et al., 1996), supported the view that chemokine receptors play an essential role as regulators of adhesion molecules, which, as a whole, allow lymphocyte subsets to navigate to different anatomical locations. These data provided the first experimental evidence that the chemokine system is involved in the functional compartmentalization of lymphoid organs (reviewed in Goodnow and Cyster, 1997). Based on these results chemokines and their receptors can be broadly divided into two functionally distinct categories. On the one hand inflammatory chemokines, induced or up-regulated by inflammatory stimuli, are responsible for recruiting cells involved in acute inflammatory reactions. On the other hand constitutive chemokines, produced in bone marrow, thymus and secondary lymphoid organs, are responsible for the homeostatic control of leukocyte traffic and for driving the encounter of cells that need to interact to generate an immune response (reviewed in Sallusto et al., 1998a).