Overlapping and selective roles of endothelial intercellular adhesion molecule-1 (ICAM-1) and ICAM-2 in lymphocyte trafficking.

The integrin LFA-1 interacts with a variety of ligands termed ICAMs. ICAM-1 and ICAM-2 are both expressed on endothelium and serve as counterreceptors during lymphocyte trafficking. In this study, we analyzed their relative contribution to lymphocyte recirculation through lymph nodes and to recruitment into lung and inflamed skin by blocking mAbs against ICAM-1 and ICAM-2 and mice deficient for ICAM-1.

Activation induces rapid and profound alterations in the trafficking of T cells.

Activation and differentiation of lymphocytes have profound effects on their trafficking. Whereas naive T cells recirculate through lymphoid organs, activated cells localize predominantly in other compartments. Here, we report that changes in migratory properties of T cells occur immediately upon activation via the TCR.

Dissemination capacity of murine lymphoma cells is not dependent on efficient homing.

The extravasation of normal lymphocytes from blood into tissues is controlled by adhesion molecules ("homing receptors") that mediate their interaction with endothelial cells. It is an intriguing question whether malignant cells use the same pathways for hematogenous dissemination and whether these molecules are involved in the organ-specific formation of metastasis. To analyze the migration behavior of lymphoma cells in vivo, we here used several lines and sublines which exhibit differential expression of the lymph node homing receptor L-selectin and the mucosa-specific integrin alpha4beta7.

Therapeutic effects of antibodies against adhesion molecules in murine collagen type II-induced arthritis.

Adhesion molecules play important roles in immune reactions and inflammatory processes and may constitute attractive targets for immunomodulatory approaches. In this study, blocking mAbs against a series of adhesion molecules were tested for their therapeutic effect on developing arthritis in a mouse model. MAbs were given for a period of 4 weeks at the time of exspected incidence of visible disease symptoms, i.

Role of alpha 4-integrins in lymphocyte homing to mucosal tissues in vivo.

Lymphocyte recirculation through different organs is thought to be regulated by adhesion molecules ("homing receptors") recognizing tissue-specific vascular addressins on endothelium. Here we show that the alpha 4/beta 7-integrin has a key role in the migration of mouse lymphocytes to mucosal sites. Homing to Peyer's patches but not to peripheral lymph nodes is inhibited by Fab fragments of mAb PS/2 against the alpha 4-integrin chain, by mAb DATK32 recognizing a combinatorial epitope on the alpha 4/beta 7-integrin, and by mAb FIB30 against the beta 7-chain.

Integrins and L-selectin in lymphocyte-endothelium interactions and homing into gut-associated tissue.

The selective entry of subpopulations and distinct differentiation stages of lymphocytes into different tissues is thought to be mediated by interaction of endothelial ligands with adhesion molecules on lymphocytes. L-selectin has been considered as a peripheral lymph node-specific homing receptor and alpha 4-integrins have been supposed to mediate entry into mucosa-associated lymphoid tissue. In vivo homing studies show that the specificity is not so clear-cut.

Lymphocyte activation and regulation of three adhesion molecules with supposed function in homing: LECAM-1 (MEL-14 antigen), LPAM-1/2 (alpha 4-integrin) and CD44 (Pgp-1).

Directed migration of lymphocytes from blood into lymph nodes and gut-associated lymphatic tissue, also referred to as homing, is subject to change following activation. Lymphocyte migration into lymphoid organs in vivo and binding to high endothelial venules in vitro is largely suppressed after short-term stimulation with phorbol esters. The observed functional alterations were correlated with changes in the expression of three putative homing receptors, LECAM-1 (MEL-14 antigen), LPAM-1/2 (alpha 4-integrin) and the murine CD44 (Pgp-1, H-CAM, Hermes-antigen equivalent) upon different modes of cellular activation.

Homing receptors reexamined: mouse LECAM-1 (MEL-14 antigen) is involved in lymphocyte migration into gut-associated lymphoid tissue.

Specific recognition molecules ("homing receptors") on lymphocytes are thought to direct selective entry of cells into different organs. The lectin-related cell adhesion molecule LECAM-1 has previously been supposed to mediate lymphocyte entry into peripheral lymph nodes and, partially, mesenteric nodes but not into Peyer's patches. Here we present evidence that in vivo the molecule is also implicated in homing of mouse lymphocytes to Peyer's patches and may have a more general role as homing receptor for high endothelial venules-bearing lymphoid tissue, but not for most non-lymphoid tissue.

Regulation of lymphocyte homing. I. Alterations in homing receptor expression and organ-specific high endothelial venule binding of lymphocytes upon activation.

Upon activation, lymphocytes display profound alterations in their in vivo migration behavior. In an attempt to understand some of the cellular mechanisms responsible for this altered behavior, in vitro stimulated lymphocytes have been analyzed for their expression of a putative homing receptor (HOR) (defined by mAb MEL-14) and for their ability to bind to specialized lymphoid organ high endothelial venules (HEV) in vitro. The results indicate that signals related to lymphocyte activation induce complex alterations in HOR expression and organ-specificity of HEV-binding: 1) submitogenic stimuli induce an increase in MEL-14 antigen expression.

Evidence for an accessory role of LFA-1 in lymphocyte-high endothelium interaction during homing.

In a variety of lymphocyte interactions, lymphocyte function-associated antigen-1 (LFA-1) plays an important role as an accessory mechanism mediating cell adhesion. We tested the possibility that LFA-1 could also be involved in the specific binding of lymphocytes to high endothelial venules (HEV) during homing. Antibodies against LFA-1 but not against various other cell surface molecules (except the putative gp90 homing receptor defined by the MEL-14 antibody) were found to inhibit in vitro adherence of lymphocytes to HEV in frozen sections of lymph nodes.

Homing receptor expression and migration of activated lymphocytes.

The experiments show that homing receptors are regulated in a complex fashion during initial cellular activation: Signals leading to blast formation induced either: --a decrease of homing receptor expression in the majority of blasts; --an increase of the Mel-14 expression in 20-40% of the blasts, and --a selective down-regulation in the capacity to bind to Peyer's patch HEV even under conditions, where binding to peripheral HEV is high. Submitogenic stimuli in partially activated cultures induce a rise in Mel-14 antigen expression and binding to peripheral node HEV, whereas Peyer's patch binding is unchanged or lowered. Thus, a selective and differential regulation of organ-specific homing receptors takes place under distinct activation conditions.

Contact interaction between lymphocytes is a general event following activation and is mediated by LFA-1.

When lymphocytes are activated in vitro, discrete cell-cell contacts are initiated which result in cluster formation. This contact interaction is found in syngeneic or allogeneic mixed leukocyte reactions as well as in mitogen-stimulated cultures (concanavalin A, periodate, lipopolysaccharide). T cells as well as B cells display the binding phenomenon.

Lymphocytes express specific antigen-independent contact interaction sites upon activation.

Cell contact between lymphocytes can be observed in the form of clustering in autologous cultures of rat or mouse lymph node cells. Mutual binding takes place in the absence of adherent cells and is displayed by B cells as well as by T cells, with the exception of immature (Lyt 1,2+) T cells. Contact formation is related to activation of the lymphocytes since thymidine-incorporating cells as well as plaque-forming cells are concentrated in the cluster cell fraction and the formation of clusters is greatly increased by periodate stimulation.