Selective differences in vascular endothelial- vs. airway epithelial-T cell adhesion mechanisms

1994 ◽  
Vol 267 (4) ◽  
pp. L422-L432 ◽  
Author(s):  
S. Nakajima ◽  
D. C. Look ◽  
W. T. Roswit ◽  
M. J. Bragdon ◽  
M. J. Holtzman
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Epithelial Cell ◽  
Vascular Endothelial ◽  
Airway Epithelial ◽  
Beta 2 ◽  
T Cell Adhesion

The basis for T cell adhesion to airway epithelial and vascular endothelial cells was studied using a quantitative flow cytometry-based assay that avoids extensive leukocyte purification and labeling. Compared with standard cell-labeling methods, the flow cytometry-based assay yielded a lower level of constitutive T cell adhesion, despite a similar level of stimulated adhesion (after T cell activation with phorbol dibutyrate) using endothelial or epithelial cell monolayers. Endothelial T cell adhesion was further increased by monolayer treatment with tumor necrosis factor-alpha (less so with interleukin-1 beta and least with interferon-gamma), whereas epithelial T cell adhesion was most sensitive to interferon-gamma. Cytokine stimulation of adhesion was invariably concentration dependent and closely matched to the cellular levels of intracellular adhesion molecule-1 (ICAM-1). Accordingly, stimulated T cell adhesion was markedly inhibited by anti-ICAM-1 or anti-beta 2-integrin antibody (95-97% inhibition for epithelial cells and 57-67% inhibition for endothelial cells) directed against ICAM-1 interaction with lymphocyte function-associated antigen-1 (LFA-1; alpha L beta 2-integrin). Residual endothelial T cell adhesion that correlated with endothelial vascular cell adhesion molecule-1 (VCAM-1) levels was blocked by an anti-alpha 4-integrin antibody directed against VCAM-1 interaction with very late activation antigen-4 (VLA-4; alpha 4 beta 1-integrin). The results suggest that 1) peripheral blood T cells without exogenous activation exhibit little LFA-1- or VLA-4-dependent adherence except to endothelial or epithelial cells expressing high levels of ICAM-1 and/or VCAM-1; and 2) differences in endothelial vs. epithelial cell mechanisms to bind activated and unactivated T cells (e.g., dependence on a mixed- vs. a single-ligand system and distinct cytokine-responsiveness of ligand levels) may help to coordinate T cell traffic to epithelial barriers.

scholarly journals Regulatory role of CD43 leukosialin on integrin-mediated T-cell adhesion to endothelial and extracellular matrix ligands and its polar redistribution to a cellular uropod

Blood ◽  
1995 ◽  
Vol 86 (6) ◽  
pp. 2228-2239 ◽  
Author(s):  
P Sanchez-Mateos ◽  
MR Campanero ◽  
MA del Pozo ◽  
F Sanchez-Madrid
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Cell Surface ◽  
Adhesion Molecule ◽  
Negative Regulator ◽  
Regulatory Role ◽  
Beta 2 ◽  
T Lymphoblasts ◽  
T Cell Adhesion

CD43 is a cell surface-associated mucin that is abundantly expressed by most leukocytes, and that appears to function as a negative regulator of cell surface interactions, providing a repulsive barrier around cells. We have analyzed herein the ability of anti-CD43 monoclonal antibody (MoAb) to upregulate both beta 1 and beta 2 integrin-mediated cell adhesion and to promote redistribution of the CD43 molecule into a cellular uropod. Engagement of CD43 with specific antibodies enhanced the cell adhesion to both 80- and 38-kD fibronectin fragments as well as to the endothelial cell ligands vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, an effect that was mediated through the alpha 5 beta 1, alpha 4 beta 1, and alpha L beta 2 integrins, respectively. This effect on cell adhesion was achieved in Jurkat leukemic T cells by anti-CD43 MoAb alone; however, in T lymphoblasts, the activation of cell adhesion required the concomitant ligation of CD3 with suboptimal doses of anti-CD3 MoAb. Immunofluorescence analysis showed that the engagement of CD43 was accompanied by a differential redistribution of CD43 into a well- defined cytoplasmic projection or uropod, whereas the beta 1 or beta 2 integrins remained uniformly located on the contact area with substrata. This change in the localization of CD43 did not require costimulation and was induced directly by engagement of CD43 in T lymphoblasts. Other stimuli of cell adhesion in the form of cross- linked anti-CD3 MoAb or phorbol esters did not induce uropod formation or CD43 redistribution. In addition, we observed that prolonged co- culture of resting peripheral blood T lymphocytes with endothelial cells, in the absence of anti-CD43 MoAb, induced uropod formation and redistribution of CD43 in T cells. Interestingly, the myosin-disrupting drug butanedione monoxime inhibited the redistribution of CD43 induced by the specific MoAb, whereas the stimulation of cell adhesion induced by engagement of CD43 was preserved in the presence of this drug. These observations indicate that the signaling inducing integrin-mediated cell adhesion by CD43 takes place independently from the receptor redistribution. Altogether, these results indicate that CD43 has a regulatory role on both integrin-mediated T-cell adhesion and cellular morphology.

scholarly journals Salicylates Inhibit Adhesion and Transmigration of T Lymphocytes by Preventing Integrin Activation Induced by Contact With Endothelial Cells

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2389-2398 ◽  
Author(s):  
Roberto Gerli ◽  
Cristina Paolucci ◽  
Paolo Gresele ◽  
Onelia Bistoni ◽  
Stefano Fiorucci ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Function ◽  
Static System ◽  
Functional Changes ◽  
And Migration ◽  
T Cell Adhesion

The inhibition of cyclooxygenase does not fully account for the spectrum of activities of nonsteroidal antiinflammatory drugs. It is evident, indeed, that regulation of inflammatory cell function may contribute in explaining some of the effects of these drugs. Tissue recruitment of T cells plays a key role in the development of chronic inflammation. Therefore, the effects of salicylates on T-cell adhesion to and migration through endothelial cell monolayers on collagen were analyzed in an in vitro static system. Aspirin and sodium salicylate reduced the ability of unstimulated T cells to adhere to and transmigrate through cytokine-activated endothelium. Although salicylates did not modify the expression of integrins on T cells, they blunted the increased adherence induced by the anti-β2monoclonal antibody (MoAb) KIM127 and prevented the appearance of an activation-dependent epitope of the CD11/CD18 complex, recognized by the MoAb 24, induced by contact with endothelial cells. Salicylates also induced an increase of intracellular calcium ([Ca2+]i) and activation of protein kinase C (PKC) in T cells, but not cell proliferation and interleukin (IL)-2 synthesis. The reduction of T-cell adhesiveness appears to be dependent on the increase in[Ca2+]i levels, as it could be reversed by blocking Ca2+ influx, but not by inhibiting PKC. Moreover, ionomycin at concentrations giving an increase in [Ca2+]i similar to that triggered by aspirin, strictly reproduced the T-cell phenotypic and functional changes induced by salicylates. Aspirin reduced T-cell adhesion and migration also ex vivo after infusion to healthy volunteers. These data suggest that the antiinflammatory activity of salicylates may be due, at least in part, to an interference with the integrin-mediated binding of resting T lymphocytes to activated endothelium with consequent reduction of a specific T-cell recruitment into inflammatory sites.

scholarly journals Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions.

1991 ◽  
Vol 113 (5) ◽  
pp. 1203-1212 ◽  
Author(s):  
Y Shimizu ◽  
W Newman ◽  
T V Gopal ◽  
K J Horgan ◽  
N Graber ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Subsets ◽  
Molecular Pathways ◽  
T Cell Adhesion

T cell adhesion to endothelium is critical to lymphocyte recirculation and influx into sites of inflammation. We have systematically analyzed the role of four receptor/ligand interactions that mediate adhesion of peripheral human CD4+ T cells to cultured human umbilical vein endothelial cells (HUVEC): T cell LFA-1 binding to ICAM-1 and an alternative ligand ("ICAM-X"), T cell VLA-4 binding to VCAM-1, and T cell binding to ELAM-1. Contributions of these four pathways depend on the activation state of both the T cell and HUVEC, and the differentiation state of the T cell. ELAM-1 plays a significant role in mediating adhesion of resting CD4+ T cells to activated HUVEC. LFA-1 adhesion dominates with PMA-activated T cells but the strength and predominant LFA-1 ligand is determined by the activation state of the HUVEC; while ICAM-1 is the dominant ligand on IL-1-induced HUVEC, "ICAM-X" dominates binding to uninduced HUVEC. Adhesion via VLA-4 depends on induction of its ligand VCAM-1 on activated HUVEC; PMA activation of T cells augments VLA-4-mediated adhesion, both in the model of T/HUVEC binding and in a simplified model of T cell adhesion to VCAM-1-transfected L cells. Unlike LFA-1 and VLA-4, ELAM-1-mediated adhesion is not increased by T cell activation. Differential expression of adhesion molecules on CD4+ T cell subsets understood to be naive and memory cells also regulates T/HUVEC adhesion. Naive T cell adhesion to HUVEC is mediated predominantly by LFA-1 with little or no involvement of the VLA-4 and ELAM-1 pathways. In contrast, memory T cells bind better to HUVEC and utilize all four pathways. These studies demonstrate that there are at least four molecular pathways mediating T/HUVEC adhesion and that the dominance/hierarchy of these pathways varies dramatically with the activation state of the interacting cells and the differentiation state of the T cell.

scholarly journals Salicylates Inhibit Adhesion and Transmigration of T Lymphocytes by Preventing Integrin Activation Induced by Contact With Endothelial Cells

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2389-2398 ◽  
Author(s):  
Roberto Gerli ◽  
Cristina Paolucci ◽  
Paolo Gresele ◽  
Onelia Bistoni ◽  
Stefano Fiorucci ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Function ◽  
Static System ◽  
Functional Changes ◽  
And Migration ◽  
T Cell Adhesion

Abstract The inhibition of cyclooxygenase does not fully account for the spectrum of activities of nonsteroidal antiinflammatory drugs. It is evident, indeed, that regulation of inflammatory cell function may contribute in explaining some of the effects of these drugs. Tissue recruitment of T cells plays a key role in the development of chronic inflammation. Therefore, the effects of salicylates on T-cell adhesion to and migration through endothelial cell monolayers on collagen were analyzed in an in vitro static system. Aspirin and sodium salicylate reduced the ability of unstimulated T cells to adhere to and transmigrate through cytokine-activated endothelium. Although salicylates did not modify the expression of integrins on T cells, they blunted the increased adherence induced by the anti-β2monoclonal antibody (MoAb) KIM127 and prevented the appearance of an activation-dependent epitope of the CD11/CD18 complex, recognized by the MoAb 24, induced by contact with endothelial cells. Salicylates also induced an increase of intracellular calcium ([Ca2+]i) and activation of protein kinase C (PKC) in T cells, but not cell proliferation and interleukin (IL)-2 synthesis. The reduction of T-cell adhesiveness appears to be dependent on the increase in[Ca2+]i levels, as it could be reversed by blocking Ca2+ influx, but not by inhibiting PKC. Moreover, ionomycin at concentrations giving an increase in [Ca2+]i similar to that triggered by aspirin, strictly reproduced the T-cell phenotypic and functional changes induced by salicylates. Aspirin reduced T-cell adhesion and migration also ex vivo after infusion to healthy volunteers. These data suggest that the antiinflammatory activity of salicylates may be due, at least in part, to an interference with the integrin-mediated binding of resting T lymphocytes to activated endothelium with consequent reduction of a specific T-cell recruitment into inflammatory sites.

Pathogenesis-Based Development of Potential Mitigation Strategies for Blinatumomab-Associated Neurologic Events (NEs)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1589-1589 ◽  
Author(s):  
Matthias Klinger ◽  
Gerhard Zugmaier ◽  
Virginie Naegele ◽  
Mariele Goebeler ◽  
Christian Brandl ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Low Grade ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Step ◽  
T Cell Adhesion

Abstract Introduction: Blinatumomab (blin), a CD19/CD3 bispecific T-cell engager (BiTE®) antibody construct, has shown clinical efficacy in patients with both B-precursor acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (NHL). NEs are known blin-associated adverse drug reactions; most NEs occur early during the first treatment cycle and are transient and fully reversible. While NEs are manageable in ALL (favorable risk/benefit profile at a maximum target dose of 28 µg/day), NEs increase in frequency and were dose-limiting in low-grade NHL. The maximum tolerated dose in NHL was 112 µg/day. Here we present translational and single-patient data for potential mitigation strategies for blin-associated NEs. Methods: Pharmacokinetic and pharmacodynamic data from blin clinical studies in NHL and ALL were combined to develop a pathogenetic model for blin-associated NEs. The mitigation potential of substances with antiadhesive properties was studied in vitro in a flow chamber system mimicking blin-induced T-cell redistribution. Three patients with low-grade NHL who had a higher risk of developing NEs due to their low peripheral blood B/T-cell ratios received concomitant pentosan polysulfate (PPS) at infusion start and dose step. ClinicalTrials.gov NCT00274742, NCT00560794, NCT01209286, NCT01471782. Results: T-cell redistribution occurred at infusion start and dose step of blin irrespective of circulating B cells. Concurrently, T cells upregulated the activation marker CD69 and the T-cell adhesion molecule LFA-1 switched from its low to intermediate affinity isoform as shown by binding of soluble ICAM-1. Blood vessel endothelial cells were activated as indicated by release of angiopoietin-2 and clinical signs of peripheral edema. Monocyte and thrombocyte redistribution were also observed. Both B and T cells were detected in cerebrospinal fluid (CSF) of some patients with NEs, and quantifiable blin concentrations were measured in CSF of some patients independent of blood-CSF barrier integrity. A low B/T-cell ratio in peripheral blood (NHL) and/or bone marrow (ALL) has been identified as a potential risk factor for developing NEs. In flow chamber experiments, addition of blin mimicked T-cell redistribution as indicated by reduced T-cell rolling velocity and increased T-cell adhesion to brain microvascular endothelial cells and by upregulation of P-selectin and ICAM-1 adhesion molecules on endothelial cells. Substances potentially interfering with interactions between T cells and endothelial cells (eg, PPS, minocycline) reversed the above-described effects to levels seen without the addition of blin. T-cell kinetics of three patients receiving concomitant PPS at infusion start and dose step showed delayed T-cell redistribution (without circulating B cells) compared with patients without PPS coadministration. These altered T-cell kinetics correlated with less severe NEs; no treatment interruptions or discontinuations were necessary. Finite PPS coadministration had no apparent negative impact on clinical response as two patients achieved an objective response, including one patient who has been in ongoing remission for more than six years. Conclusion: We propose an evidence-based model for the development of blin-associated NEs: 1) First exposure to blin or dose steps increase endothelial adhesiveness of circulating T cells. 2) Adhering T cells activate the endothelium and start extravasating; activated endothelium attracts other circulating leukocytes. 3) At low B/T-cell ratios, extravasated T cells first encountering (rare) B cells in the brain are activated by blin in the perivascular space to locally secret cytokines and chemokines that induce transient neuroinflammation including transmigration of monocytes. 4) Attracted non-T cells and other released factors enhance transient neurotoxicity. Based on this model, T-cell adhesion to blood vessel endothelial cells is the first necessary (but not sufficient) step in the pathogenesis of blin-associated NEs. Coadministration of substances with antiadhesive properties at infusion start and dose steps may offer opportunities to mitigate blin-associated NEs to further improve the safety and efficacy of blin therapy. Disclosures Klinger: Amgen Research (Munich) GmbH: Employment, Equity Ownership, Patents & Royalties: Blinatumomab. Zugmaier:Amgen: Employment, Patents & Royalties. Naegele:Amgen Research (Munich) GmbH: Employment, Equity Ownership, Patents & Royalties. Goebeler:GEmoAb: Consultancy; Novartis: Consultancy; Roche: Consultancy. Brandl:Amgen: Employment. Kufer:AMGEN Research Munich: Employment, Equity Ownership, Patents & Royalties.

scholarly journals CD31 expressed on distinctive T cell subsets is a preferential amplifier of beta 1 integrin-mediated adhesion.

1992 ◽  
Vol 176 (1) ◽  
pp. 245-253 ◽  
Author(s):  
Y Tanaka ◽  
S M Albelda ◽  
K J Horgan ◽  
G A van Seventer ◽  
Y Shimizu ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
Endothelial Cell ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Adhesion Molecule ◽  
T Cell Subsets ◽  
Beta 2 ◽  
Endothelial Cell Adhesion

The CD31 (platelet endothelial cell adhesion molecule-1 [PECAM-1]/endothelial cell adhesion molecule [endoCAM]) molecule expressed on leukocytes, platelets, and endothelial cells is postulated to mediate adhesion to endothelial cells and thereby function in immunity, inflammation, and wound healing. We report the following novel features of CD31 which suggests a role for it in adhesion amplification of unique T cell subsets: (a) engagement of CD31 induces the adhesive function of beta 1 and beta 2 integrins; (b) adhesion induction by CD31 immunoglobulin G (IgG) monoclonal antibodies (mAbs) is sensitive, requiring only bivalent mAb; (c) CD31 mAb induces adhesion rapidly, but it is transient; (d) unique subsets of CD4+ and CD8+ T cells express CD31, including all naive (CD45RA+) CD8 T cells; and (e) CD31 induction is selective, inducing adhesive function of beta 1 integrins, particularly very late antigen-4, more efficiently than the beta 2 integrin lymphocyte function-associated antigen-1. Conversely, CD3 is more effective in inducing beta 2-mediated adhesion. Taken together, these findings indicate that unique T cell subsets express CD31, and CD31 has the capacity to induce integrin-mediated adhesion of T cells in a sensitive and selective fashion. We propose that, in collaboration with other receptors/ligands, CD31 functions in an "adhesion cascade" by amplifying integrin-mediated adhesion of CD31+ T cells to other cells, particularly endothelial cells.

Regulation of epithelial and lymphocyte cell adhesion by adenosine deaminase–CD26 interaction

2002 ◽  
Vol 361 (2) ◽  
pp. 203-209 ◽  
Author(s):  
Silvia GINÉS ◽  
Marta MARIÑO ◽  
Josefa MALLOL ◽  
Enric I. CANELA ◽  
Chikao MORIMOTO ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Cell Surface ◽  
Adenosine Deaminase ◽  
Cell To Cell Adhesion ◽  
Lymphocyte Cell

The extra-enzymic function of cell-surface adenosine deaminase (ADA), an enzyme mainly localized in the cytosol but also found on the cell surface of monocytes, B cells and T cells, has lately been the subject of numerous studies. Cell-surface ADA is able to transduce co-stimulatory signals in T cells via its interaction with CD26, an integral membrane protein that acts as ADA-binding protein. The aim of the present study was to explore whether ADA—CD26 interaction plays a role in the adhesion of lymphocyte cells to human epithelial cells. To meet this aim, different lymphocyte cell lines (Jurkat and CEM T) expressing endogenous, or overexpressing human, CD26 protein were tested in adhesion assays to monolayers of colon adenocarcinoma human epithelial cells, Caco-2, which express high levels of cell-surface ADA. Interestingly, the adhesion of Jurkat and CEM T cells to a monolayer of Caco-2 cells was greatly dependent on CD26. An increase by 50% in the cell-to-cell adhesion was found in cells containing higher levels of CD26. Incubation with an anti-CD26 antibody raised against the ADA-binding site or with exogenous ADA resulted in a significant reduction (50–70%) of T-cell adhesion to monolayers of epithelial cells. The role of ADA—CD26 interaction in the lymphocyte—epithelial cell adhesion appears to be mediated by CD26 molecules that are not interacting with endogenous ADA (ADA-free CD26), since SKW6.4 (B cells) that express more cell-surface ADA showed lower adhesion than T cells. Adhesion stimulated by CD26 and ADA is mediated by T cell lymphocyte function-associated antigen. A role for ADA—CD26 interaction in cell-to-cell adhesion was confirmed further in integrin activation assays. FACS analysis revealed a higher expression of activated integrins on T cell lines in the presence of increasing amounts of exogenous ADA. Taken together, these results suggest that the ADA—CD26 interaction on the cell surface has a role in lymphocyte—epithelial cell adhesion.

scholarly journals Patterns for RANTES Secretion and Intercellular Adhesion Molecule 1 Expression Mediate Transepithelial T Cell Traffic Based on Analyses In Vitro and In Vivo

1998 ◽  
Vol 187 (12) ◽  
pp. 1927-1940 ◽  
Author(s):  
Masahiko Taguchi ◽  
Deepak Sampath ◽  
Takeharu Koga ◽  
Mario Castro ◽  
Dwight C. Look ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Cell Surface ◽  
Immune Cell ◽  
Intercellular Adhesion Molecule ◽  
Airway Epithelial ◽  
Intercellular Adhesion Molecule 1 ◽  
Ifn Γ

Immune cell migration into and through mucosal barrier sites in general and airway sites in particular is a critical feature of immune and inflammatory responses, but the determinants of transepithelial (unlike transendothelial) immune cell traffic are poorly defined. Accordingly, we used primary culture airway epithelial cells and peripheral blood mononuclear cells to develop a cell monolayer system that allows for apical-to-basal and basal-to-apical T cell transmigration that can be monitored with quantitative immunofluorescence flow cytometry. In this system, T cell adhesion and subsequent transmigration were blocked in both directions by monoclonal antibodies (mAbs) against lymphocyte function-associated antigen 1 (LFA-1) or intercellular adhesion molecule 1 (ICAM-1) (induced by interferon γ [IFN-γ] treatment of epithelial cells). The total number of adherent plus transmigrated T cells was also similar in both directions, and this pattern fit with uniform presentation of ICAM-1 along the apical and basolateral cell surfaces. However, the relative number of transmigrated to adherent T cells (i.e., the efficiency of transmigration) was increased in the basal-to-apical relative to the apical-to-basal direction, so an additional mechanism was needed to mediate directional movement towards the apical surface. Screening for epithelial-derived β-chemokines indicated that IFN-γ treatment caused selective expression of RANTES (regulated upon activation, normal T cell expressed and secreted), and the functional significance of this finding was demonstrated by inhibition of epithelial–T cell adhesion and transepithelial migration by anti-RANTES mAbs. In addition, we found that epithelial (but not endothelial) cells preferentially secreted RANTES through the apical cell surface thereby establishing a chemical gradient for chemotaxis across the epithelium to a site where they may be retained by high levels of RANTES and apical ICAM-1. These patterns for epithelial presentation of ICAM-1 and secretion of RANTES appear preserved in airway epithelial tissue studied either ex vivo with expression induced by IFN-γ treatment or in vivo with endogenous expression induced by inflammatory disease (i.e., asthma). Taken together, the results define how the patterns for uniform presentation of ICAM-1 along the cell surface and specific apical sorting of RANTES may serve to mediate the level and directionality of T cell traffic through epithelium (distinct from endothelium) and provide a basis for how this process is precisely coordinated to route immune cells to the mucosal surface and maintain them there under normal and stimulated conditions.

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