Integrins and their function in leukocyte trafficking

The function of the immune system depends on tissue-specific leukocyte recruitment and microenvironmenteal positioning. In turn, recruitment and positioning of leukocytes to sites of immune response relies on cell adhesion and motility, which are both critically dependent on rapid integrin activation and engagement. Integrins are ubiquitously expressed, highly versatile transmembrane heterodimeric receptors (1) (Table I). The most relevant integrins to immune system regulation are the β2 integrins Mac-1 (CR3, CD11b/CD18) and LFA-1 (CD11a/CD18), the β1 integrin VLA-4 (CD49d/CD29) and the β7 integrin α4β7. These integrins regulate a variety of processes. For instance, they act as costimulatory molecules for T cell receptors in the immunological synapse (2), mediate interactions with bacteria (3) and phagocytosis (4), and support leukocyte adhesion to the endothelium and transendothelial migration during lymphocyte homing (5). In this last case, integrins have a dual role: a) they are the "ultimate brakes" for circulating leukocytes, stably arresting interacting cells on the endothelium; and b) they contribute to the diversity in leukocyte recruitment. It is important to emphasize that each of these cellular events shows different kinetics. For instance, the assembly of the immunological synapse, which involves LFA-1 surface redistribution and accumulation at the periphery of the synapse, takes several minutes (6, 7). In contrast, the rapid arrest of circulating leukocytes on the endothelium occurs in a few seconds or less. These different kinetics in cellular phenomena imply distinct kinetics of integrin activation and different modalities of integrin triggering. Although it is likely that the final, proximal to the eterodimer, molecular event leading to integrin activation is common, as we will see later, it is quite likely that different kinetics of integrin activation observed in different phenomena depend on activation of distinct, agonist-specific, intracellular signaling networks. For instance, chemokines, the fastest physiologic integrin activators, trigger proadhesive signaling events much more rapidly than phorbol esters, that triggers integrins with slower kinetics (8). Thus, a comprehensive understanding of the role of integrin activation in leukocyte physiology needs to correlate the kinetics of adhesion triggering to the kinetics of signaling networks. As rapid integrin triggering plays a crucial role in leukocyte trafficking, we will mainly focus on mechanisms of rapid and reversible integrin activation and on cross-talk between integrins and chemokine receptors.