Mucosal lymphocyte homing

Lymphocytes of B and T lineages recirculate via the bloodstream and re-enter secondary lymphoid tissues. This lymphocyte homing of naive cells insures that a diverse repertoire exists in mucosal and peripheral lymphoid tissues, while homing of memory and effector cells is responsible for keeping lymphocytes compartmentalized, i.e. mucosal in the mucosa and peripheral in the periphery. It is now clear that lymphocytes leave the blood and enter lymphoid compartments (usually via HEVs) in a multistep extravasation process. Homing is dependent upon the expression of adhesion molecules such as selectins and integrins, collectively termed 'homing receptors' on lymphocytes, with specific ligands on HEV and venule endothelial cells which are collectively termed 'addressins'.

Some generalizations can be made to this rapidly changing area. First, naive T and B lymphocytes can express homing receptors for addressins on either peripheral or mucosal inductive tissues, i.e. peripheral lymph nodes versus Peyer's patches. It is generally accepted that naive lymphocytes can recirculate between secondary lymphoid tissues; however only memory or effector lymphocytes have receptor-ligands for movement into certain microenviron-ments such as lamina propria or the epithelium of the intestinal mucosa. Peripheral lymphocyte homing is mainly controlled by expression of L-selectin and the ligand peripheral lymph node addressin (PNAd); however, other receptors and ligands are also involved. Naive mucosal lymphocytes express (37-integrin family members, particularly [email protected] Peyer's patch HEVs and gastrointestinal tract lamina propria express the mucosal addressin cell adhesion molecule (MAdCAM-t) which serves as the specific ligand for a4|37. Interestingly, mucosa-derived memory lymphocytes express higher levels of a4p7, which presumably allows for binding to MAdCAM-1 on PP HEVs as well as to the low level expression of this addressin on lamina propria venules in the gastrointestinal tract. Although «4P7-MAdCAM-1 are the major receptor-ligand for mucosal homing in the gastrointestinal tract, other receptor-ligand combinations are also involved.

A second (37-integrin, aK|37 is expressed on >98% of human intraepithelial lymphoyctes (IELs, see below) and the ligand for this homing receptor is E-cadherin expressed on the basolateral portion of epithelial cells. It has been shown that TGFfJ markedly enhances the expression of aE|37 on IELS, and thus promotes their increased adherence to epithelial cells.

Perhaps the most intriguing aspect of mucosal lymphocyte homing is that no lung-specific integrins have yet been identified. Further, the homing receptors present on BALT (in rabbits) and NALT (in humans) which directs mucosal lymphocytes to other regions, e.g. the lungs and the genitourinary tract, remain to be fully defined. Nevertheless, it is known that intranasal immunization is quite effective for induction of mucosal IgA responses in the upper respiratory and the female reproductive tracts. It is tempting to suggest that NALT lymphocytes bear homing receptors for addressins expressed in these mucosal effector sites. Clearly other integrins and addressins may be involved and may ultimately explain how MALT cells from NALT redistribute more frequently to certain effector sites, while GALT repopulate common as well as different mucosal effector sites.

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