Adhesion Molecule Interactions Play Critical Roles in Extravasation

The extravasation of lymphocytes into secondary lymphoid tissue or regions of inflammation is a multistep process involving a cascade of adhesion-molecule interactions similar to those involved in neutrophil emigration from the blood stream. Figure 15-7 depicts the typical interactions in extravasation of naive T cells across HEVs into lymph nodes. The first step is usually a selectin-carbohydrate interaction similar to that seen with neutrophil adhesion. Naive lymphocytes initially bind to HEVs by L-selectin, which serves as a homing receptor that directs the lymphocytes to particular tissues expressing a corresponding mucin-like vascular ad-dressin such as CD34 or GlyCAM-1. Lymphocyte rolling is less pronounced than that of neutrophils. Although the initial selectin-carbohydrate interaction is quite weak, the slow rate of blood flow in postcapillary venules, particularly in regions of HEVs, reduces the likelihood that the shear force of the flowing blood will dislodge the tethered lymphocyte.

In the second step, an integrin-activating stimulus is mediated by chemokines that are either localized on the endothelial surface or secreted locally. The thick glycocalyx covering of the HEVs may function to retain these soluble chemoattractant factors on the HEVs. If, as some have proposed, HEVs secrete lymphocyte-specific chemoattractants, it would explain why neutrophils do not extravasate into lymph nodes at the HEVs even though they express L-selectin. Chemokine binding to G-protein-coupled receptors on the lymphocyte leads to activation of integrin molecules on the membrane, as occurs in neutrophil extravasation. Once activated, the integrin molecules interact with Ig-superfamily adhesion molecules (e.g., ICAM-1), so the lymphocyte adheres firmly to the endothe-lium. The molecular mechanisms involved in the final step, transendothelial migration, are poorly understood.

Rolling

Naive CD

Activation

Arrest/adhesion

Rolling

Naive CD

Activation

Arrest/adhesion

Lymphocytes Extravasation

Steps in extravasation of a naive T cell through a high-endothelial venule into a lymph node. Extravasation of lymphocytes includes the same basic steps as neutrophil extravasation but some of the cell-adhesion molecules differ. Activation of the integrin LFA-1, induced by chemokine binding to the lymphocyte, leads to firm adhesion followed by migration between the endothelial cells into the tissue.

FIGURE 15-7

Steps in extravasation of a naive T cell through a high-endothelial venule into a lymph node. Extravasation of lymphocytes includes the same basic steps as neutrophil extravasation but some of the cell-adhesion molecules differ. Activation of the integrin LFA-1, induced by chemokine binding to the lymphocyte, leads to firm adhesion followed by migration between the endothelial cells into the tissue.

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