The lymphocyte homing receptors: gatekeepers of the multistep paradigm

Lymphocyte trafficking is regulated by adhesion molecules mediating the initial shear-resistant binding of circulating cells to target tissue endothelium (Step 1). This review focuses on the current and emerging perspectives of the biology of these 'homing receptors.'

The conventional multistep paradigm holds that leukocyte migration represents a cascade of events, initiated by tethering and rolling interactions of leukocytes on the endothelial surface (Step 1). These interactions are indispensable, required to dampen velocities sufficiently to allow cells to sense the local chemokines and/or other inflammatory signals resulting in activation of integrin adhesiveness (Step 2), with ensuing firm adherence on the vessel wall (Step 3) followed by endothelial transmigration (Step 4). Mechanistic studies now suggest that some effectors of Step 1 interactions themselves activate integrin adhesiveness and trigger transmigration--in some cases by forming complexes with integrins--thus bypassing the need for chemokine signaling. These findings force a reconsideration of the multistep paradigm, and shift focus now to identifying all relevant effectors of Step 1 interactions using adherence assays performed under shear stress to mimic the dynamic conditions of blood flow.

Recent findings suggest that homing receptors are not merely molecular brakes. The cross-talk among the homing receptors and integrins opens a new 'avenue' to lymphocyte migration, suggesting that homing receptors may be sufficient alone, in some cases, to perform the function the name implies.