Abstract :
It is now well recognized that the process of lymphocyte migration is not random event but a complex phenomenon finely tuned to facilitate the extravasation of distinct lymphocyte subsets to particular tissues where specialized immune/inflammatory responses take place. The most striking example of diversity in lymphocyte trafficking comes from the preferential recirculation of naive versus activated/memory populations. While naive lymphocytes (CD45RA+) principally migrate to secondary lymphoid tissues, activated/memory T cells (CD45R0+) preferentially migrate to peripheral tissues. However, phenotypic analysis of the lymphocytes found at sites of inflammation indicates that distinct sub-subsets of memory T cells accumulate into different tissues such as lung, gut, skin and joint. The reasons for this are not completely understood but it is thought that regulatory mechanisms intervene at least at three different levels. The first level of control, which is the subject of this presentation, relates to specific lymphocyte-endothelial recognition systems operating in the microvascular beds of various tissues. A second level of regulation may involve the local production of specific chemoattractants capable of recalling lymphocytes programmed to recirculate to a given compartment. A final control mechanism can be exerted once lymphocytes have reached the tissues where specific subsets of cells can be preferentially retained by binding to selective tissue ligands.
Before reaching the tissues, however, lymphocyte have to overcome the shear forces in the circulation, adhere and migrate through the endothelial and basal membrane vascular barrier. This process, regulated by different families of adhesion molecules, has been divided in four sequential steps: (I) primary adhesion, (II) lymphocyte activation, (III) secondary or firm adhesion and (IV) diapedesis. In the first step, cells are tethered to the endothelium by selectin molecules which adhere to cognate carbohydrate determinants. This interaction is of low affinity and activation-independent but sufficient to allow lymphocytes to roll onto the endothelium. In this way the local micro-environment can be sampled for the presence or absence of inflammatory mediators. In their absence, cells detach and are carried by the flow. If tissue are inflamed chemokines can, through G protein linked receptors, trigger step number two: the activation of integrin molecules. This induces an increase in binding affinity of these molecules which strongly interact with the immunoglobulin superfamily counter-receptors causing the arrest of the rolling lymphocytes (third step). Only at this stage cells are capable of transmigration (fourth step).
Although these mechanisms are capable of controlling migration universally the diverse extravasation into different tissues is additionally regulated by the specific interaction of lymphocyte “homing” receptors and endothelial “addressin” ligands. Some example of this include the interaction of a) L-selectin with GlyCAMʹs molecules, which mediate migration into peripheral lymph nodes, b) α4β7 with MAdCAM-1, which controls migration to intestinal tissues, and C) CLA with E-selectin, which facilitates extravasation into the skin. It should be mentioned that some of these molecules can assist in both homing functions and primary or secondary adhesion. Furthermore, quantitative as well as qualitative regulation of receptors is important in favouring lymphocyte extravasation. Such fine regulation allows the coexistence of universal migration and specific homing mechanisms which enable the development of immune responses in specialized compartments while permitting their integration throughout the body.
