Molecular Determinants Controlling Homeostatic Recirculation and Tissue-Specific Trafficking of Lymphocytes

Abstract

The homeostasis of the immune system is maintained by the recirculation of naïve lymphocytes through the secondary lymphoid tissues, such as the lymph nodes, Peyer’s patches, and spleen. Upon insult by pathogens or antigens, lymphocytes become activated, and the regulated trafficking of these cells results in the integration of systemic and regional immune responses. The exquisite specificity of such lymphocyte trafficking is determined by tissue-specific guidance signals expressed by the endothelial cells of postcapillary venules, combined with counterreceptors expressed by the circulating lymphocytes. The high endothelial venules can selectively guide naïve lymphocytes into the lymph nodes and Peyer’s patches by expressing a unique combination of vascular addressins, lymphocyte-specific chemokines, and chemokine-binding molecules. The inflamed postcapillary venules in extralymphoid tissues, such as the skin and intestinal lamina propria, also use a distinct array of endothelial adhesion molecules and tissue- selective chemokines, and support the recruitment of effector and memory lymphocytes that express the appropriate receptors for tissue-specific trafficking. In this review, we summarize the present understanding of the homeostatic recirculation of naïve lymphocytes through the secondary lymphoid tissues and the specific targeting of antigen-experienced lymphocytes into the effector sites. We also revisit some previous studies that reported apparently conflicting observations.

Fas/Fas Ligand–mediated Apoptosis in Different Cell Lineages and Functional Compartments of Human Lymph Nodes

“…There are now five different pieces of evidence favoring the idea that FasL expression in lymph node HEVs induces apoptosis in activated lymphocytes entering the lymph node parenchyma: (1) Activated lymphocytes are not able to migrate into lymph node parenchyma (Mackay 1991;Tanaka et al 2004); (2) In inactivating mutations of the Fas gene, both in mouse and in humans, lymph nodes are enlarged with paracortical expansion (Le Deist et al 1996;Sneller et al 1997); (3) HEVs express Fas ligand in the lymph node paracortex (Kokkonen et al 2004); (4) Most paracortical (near-HEV) apoptotic cells express Fas, as shown here; (5) Similarly, in immune-privileged sites, FasL in epithelium provides protection against the inflammatory process (Abbas 1996;Ferguson and Griffith 2006). About 50% of the germinal center apoptotic cells showed expression of CD20, a marker of mature Blymphocytes, and ?20% expressed CD19, a marker of immature B-lymphocytes, indicating that a majority of apoptotic cells in germinal centers are of B-lymphocyte lineage.…”

Regulation of Immune Response and Inflammatory Reactions against Viral Infection by VCAM-1

“…Leukocyte trafficking is a dynamic multistep process of leukocyte rolling on the vascular endothelium, followed by activation, adherence, and transmigration into tissue (15,31,34,35,39,51,56,66,67). In particular, leukocyte recruitment into specific tissues is determined by integrin-mediated firm adhesion (2,7,20,31,33,39,42,43,46,73).…”

Binding of Lymphoid Chemokines to Collagen IV That Accumulates in the Basal Lamina of High Endothelial Venules: Its Implications in Lymphocyte Trafficking

“…L ymphocytes continuously recirculate between the blood and the lymph by way of the secondary lymphoid tissues, where Ags and APCs are selectively localized (1)(2)(3). To enter lymph nodes (LN) 3 and Peyer's patches (PP), lymphocytes in the blood selectively adhere to and transmigrate across high endothelial venules (HEV) in which certain lymphoid chemokines are constitutively expressed; these chemokines play a critical role in lymphocyte trafficking to the LNs and PPs (4 -7).…”

“…To enter lymph nodes (LN) 3 and Peyer's patches (PP), lymphocytes in the blood selectively adhere to and transmigrate across high endothelial venules (HEV) in which certain lymphoid chemokines are constitutively expressed; these chemokines play a critical role in lymphocyte trafficking to the LNs and PPs (4 -7).…”