The Multistep Paradigm of Lymphocyte Extravasation
Lymphocyte extravasation is initiated by transient interactions with the blood vessels through adhesion receptors including selectins and their ligands, members of the inte-grin superfamily, and the vascular hyaluronan-binding CD44. By virtue of these interactions T cells tether the vascular wall where they are exposed to chemokines (chemotactic cytokines), bound to the endothelial cell (EC) surface by glycosaminoglycans (GAGS). Chemokines trigger pertussis toxin-sensitive G-protein coupled receptors on the T cells. This "activation" event leads to conformational changes in the T-cell integrin adhesion molecules (including members of the p2 and pi family of integrins, such as LFA-1 and VLA-4) that increase their affinity for their ligands. Chemokines also induce changes in the T cell shape (from round and villous to polarized), which create an ideal sur face of interaction between T cells and ECs. As a consequence T cells flatten over and firmly adhere to the endothe-lium. Additional molecular interactions involving adhesion molecules (including integrins and junction adhesion molecules) and chemokines guide the migration of the adherent lymphocyte through the endothelial junctions (transendothe-lial migration or diapedesis). Some EC molecules such as CD31 appear to optimize the efficiency of this last step of the migratory process. A summary of the T cell-EC interactions leading to T-cell extravasation is provided in Figure 1. Together with intrinsic properties of the T cells (such as the high expression of certain adhesion molecules, as observed in memory T cells), signals mediated by these relatively well-characterized ligand-receptor interactions are likely to determine whether a T cell that is engaging in adhesive interactions with EC will eventually migrate into the underlying tissue.
T Lymphocyte Phenotype and Function is Modified By Transendothelial Migration
Once T cells have crossed the endothelial barrier, they remain localized for a variable length of time between the endothelial layer and the basal membrane and eventually enter the tissue. Tissue infiltration is a slow and complex process, which involves T-cell interactions with the basal membrane and the extracellular matrix and migration induced by tissue-derived chemokines. Thus, once a T cell has crossed the endothelial barrier and is committed to migration, it undergoes a genetic reprogramming leading to functional changes including induction of matrix metallo-proteinase (MMP) expression, and responsiveness to tissue-derived chemoattractants that enable them to invade the
i. Rolling: ii. Exposure to iii. Firm adhesion: iv- Diapedesis.
selectins chemokines (activation): integrins integrins, CTOl, JAMs integrins integrin activation, TCR triggering cell polarization i. Rolling: ii. Exposure to iii. Firm adhesion: iv- Diapedesis.
selectins chemokines (activation): integrins integrins, CTOl, JAMs integrins integrin activation, TCR triggering cell polarization v. Tissue infiltration:
integrins, chemokines, MMP
Figure 1 The multistep paradigm of lymphocyte extravasation. T cells are first engaged in selectin-mediated transient interactions with the endothelium. In this way, they become exposed to endothelium-bound chemokines. This induces increased affinity of T-cell integrin for their endothelial ligands and causes T-cell polarization (i.e., change of shape and redistribution of surface molecules). T cells thus firmly adhere to the endothelium and eventually migrate through the endothelial cell junctions. Once in the tissue, T lymphocytes respond to stimuli that lead them to the site of inflammation. (see color insert)
tissue and reach the inflammatory site. It is likely that the endothelium itself delivers the necessary signals to transiting T cells, which favor T-cell motility and further infiltration of the underlying tissue. In this context, upregulation of certain molecules (including at the transcriptional level), such as CD86 and CD69, has been observed in T cells following noncognate interactions with the EC. These changes are likely to help further activation of the T cells once they have reached their antigenic sites within the tissue. In line with these studies, we have observed that T-cell transendothelial migration is accompanied by activation of the transcription factor AP-1, without induction of NF-kB. This genetic reprogramming correlates with the upregulation of certain adhesion (LFA-1, VLA-4), activation (CD69), and costimulatory (CD86) receptors and with increased T-cell motility and antigen responsiveness to tissue invasiveness. These effects were dependent on aLß2 integrin/CD54 interactions during adhesion to the endothelium.
Thus, T-cell extravasation is accompanied by phenotypic and functional changes induced by the interactions with the EC, which favor tissue infiltration by T cells and their further activation once they reach the antigenic site. The nature of the endothelium-derived signals that induces "proinvasive" genetic reprogramming in T lymphocytes and the molecular changes required for tissue invasion by T cells remain poorly characterized.
Recirculation of Memory and Naive T Cells and Tissue-Specific Homing
The ability of T lymphocytes to reach antigenic tissue is regulated at different levels. Naive T cells recirculate through secondary lymphoid organs (spleen, lymph nodes, and Peyer's patches) through the expression of L-selectin (CD62L) and the chemokine receptor CCR7. Expression of their ligand is restricted to the microvasculature of secondary lymphoid organs. Following antigen encounter and activation in the lymphoid tissues, changes are induced in the array of surface-expressed adhesion receptors, which allow effector memory T-cell access into nonlymphoid tissue. These changes include loss of CD62L and CCR7 expression and upregulation of other adhesion (LFA-l) and chemokine (CXCR4, CCR5) receptors. It has recently been described that a subset of memory T cells (central memory T cells) retain expression of the chemokine receptor CCR7 and the ability to traffic through secondary lymphoid organs. Finally, a third subset of memory T lymphocytes differentiates following priming in the lymph nodes, namely the fol-licular homing T cells, which specialize in delivering help to B cells. These cells are retained in the lymphoid tissue characterized by the expression of the chemokine receptor CXCR5, which mediates their recruitment in the B cell areas of the lymph node.
Memory and effector T cells generally display selective tropism for specific peripheral tissue such as the skin or the gut (tissue-specific homing). This is mediated by the use of different combinations of adhesion and chemokine receptors (molecular "area code") at distinct anatomical sites that facilitate the T lymphocyte return to that site. For example, high-level expression of a4b7 integrin, whose ligand mucosal addressin cell adhesion molecule (MAdCAM)-l is expressed on postcapillary venules in the intestinal lamina propria, targets one population of memory T cells to this site. In addition, a subset of these intestinal a4b7hi cells also expresses CCR9, the specific receptor for the chemokine CCL25, or thymus-expressed chemokine (TECK), which is produced by small intestinal epithelium. In contrast, memory and effector cell recruitment to inflamed skin requires expression of lymphocyte surface lig-ands for vascular selectins, such as the E-selectin ligand cutaneous lymphocyte antigen (CLA) in humans and P-selectin ligand in mice. In addition, skin-homing T cells express CCR4, the specific receptor for the chemokine CCL17, or thymus and activation-regulated chemokine (TARC), expressed by keratinocytes. T cells acquire these receptors during priming in the lymphoid tissue. The genetic reprogramming leading to the acquisition of a molecular area code is determined by the local lymphoid organ microenvironment.
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