scholarly journals A Novel Endothelial L-Selectin Ligand Activity in Lymph Node Medulla That Is Regulated by α(1,3)-Fucosyltransferase-IV

2003 ◽  
Vol 198 (9) ◽  
pp. 1301-1312 ◽  
Author(s):  
Christine M'Rini ◽  
Guiying Cheng ◽  
Colleen Schweitzer ◽  
Lois L. Cavanagh ◽  
Roger T. Palframan ◽  
...  
Keyword(s):  
Mrna Level ◽  
Surrogate Marker ◽  
High Endothelial Venules ◽  
Cell Homing ◽  
Selectin Ligands ◽  
Peripheral Lymph ◽  
T Cell Homing ◽  
Selectin Ligand ◽  
Peripheral Node ◽  
Ligand Activity

Lymphocytes home to peripheral lymph nodes (PLNs) via high endothelial venules (HEVs) in the subcortex and incrementally larger collecting venules in the medulla. HEVs express ligands for L-selectin, which mediates lymphocyte rolling. L-selectin counterreceptors in HEVs are recognized by mAb MECA-79, a surrogate marker for molecularly heterogeneous glycans termed peripheral node addressin. By contrast, we find that medullary venules express L-selectin ligands not recognized by MECA-79. Both L-selectin ligands must be fucosylated by α(1,3)-fucosyltransferase (FucT)-IV or FucT-VII as rolling is absent in FucT-IV+VII−/− mice. Intravital microscopy experiments revealed that MECA-79–reactive ligands depend primarily on FucT-VII, whereas MECA-79–independent medullary L-selectin ligands are regulated by FucT-IV. Expression levels of both enzymes paralleled these anatomical distinctions. The relative mRNA level of FucT-IV was higher in medullary venules than in HEVs, whereas FucT-VII was most prominent in HEVs and weak in medullary venules. Thus, two distinct L-selectin ligands are segmentally confined to contiguous microvascular domains in PLNs. Although MECA-79–reactive species predominate in HEVs, medullary venules express another ligand that is spatially, antigenically, and biosynthetically unique. Physiologic relevance for this novel activity in medullary microvessels is suggested by the finding that L-selectin–dependent T cell homing to PLNs was partly insensitive to MECA-79 inhibition.

scholarly journals Sialomucin CD34 is the major L-selectin ligand in human tonsil high endothelial venules.

1995 ◽  
Vol 131 (1) ◽  
pp. 261-270 ◽  
Author(s):  
K D Puri ◽  
E B Finger ◽  
G Gaudernack ◽  
T A Springer
Keyword(s):  
Complex Mixture ◽  
Lymphocyte Homing ◽  
High Endothelial Venules ◽  
Human Tonsil ◽  
Hematopoietic Cell Line ◽  
Selectin Ligands ◽  
Selectin Ligand ◽  
Peripheral Node ◽  
Ligand Activity

Peripheral node addressin (PNAd) is a complex mixture of glycoproteins with L-selectin ligand activity that functions in lymphocyte homing. We have investigated the contribution of the sialomucin CD34 relative to other components of PNAd in lymphocyte tethering and rolling in in vitro laminar flow assays. PNAd was isolated with MECA-79 mAb-Sepharose from tonsillar stroma, and the CD34 component (PNAd,CD34+) and CD34-negative component (PNAd,CD34-) separated on CD34 mAb-Sepharose. Lymphocytes on the PNAd,CD34- fraction tether less efficiently, roll faster and are less resistant to shear detachment than on PNAd. The PNAd,CD34+ fraction constitutes about half the total functional activity. These studies show that CD34 is a major functional component of PNAd. Ligand activity in both the PNAd,CD34+ and PNAd,CD34- fractions is expressed on mucin-like domains, as shown with O-sialoglycoprotease. The CD34 component of PNAd has about four times higher tethering efficiency than total tonsillar CD34. CD34 from spleen shows no lymphocyte tethering. Although less efficient than the PNAd,CD34+ fraction from tonsil, CD34 from the KG1a hematopoietic cell line is functionally active as an L-selectin ligand despite lack of reactivity with MECA-79 mAb, which binds to a sulfation-dependent epitope. All four forms of CD34 are active in binding to E-selectin. KG1a CD34 but not spleen CD34 are active as L-selectin ligands, yet both lack MECA-79 reactivity and possess E-selectin ligand activity. This suggests that L-selectin ligands and E-selectin ligands differ in more respects than presence of the MECA-79 epitope.

Sulphated endothelial ligands for L-selectin in lymphocyte homing and inflammation

2003 ◽  
Vol 31 (2) ◽  
pp. 313-317 ◽  
Author(s):  
A. van Zante ◽  
S.D. Rosen
Keyword(s):  
Monoclonal Antibody ◽  
Endothelial Cells ◽  
Lymphoid Tissues ◽  
Lymphocyte Homing ◽  
High Endothelial Venules ◽  
Selectin Ligands ◽  
Peripheral Lymph ◽  
Selectin Ligand ◽  
Endothelial Ligands ◽  
Peripheral Node

Lymphocytes from the blood home to secondary lymphoid tissues through a process of tethering, rolling, firm adhesion and transmigration. Tethering and rolling of lymphocytes is mediated by the interaction of L-selectin on lymphocytes with sulphated ligands expressed by the specialized endothelial cells of high endothelial venules (HEVs). The sulphate-dependent monoclonal antibody MECA79 stains HEVs in peripheral lymph nodes and recognizes the complex of HEV ligands for L-selectin termed peripheral node addressin. High endothelial cell GlcNAc-6-sulphotransferase/L-selectin ligand sulphotransferase is a HEV-expressed sulphotransferase that contributes to the formation of the MECA79 epitope and L-selectin ligands on lymph node HEVs. MECA79-reactive vessels are also common at sites of chronic inflammation, suggesting mechanistic parallels between lymphocyte homing and inflammatory trafficking.

scholarly journals The Cc Chemokine Thymus-Derived Chemotactic Agent 4 (Tca-4, Secondary Lymphoid Tissue Chemokine, 6ckine, Exodus-2) Triggers Lymphocyte Function–Associated Antigen 1–Mediated Arrest of Rolling T Lymphocytes in Peripheral Lymph Node High Endothelial Venules

2000 ◽  
Vol 191 (1) ◽  
pp. 61-76 ◽  
Author(s):  
Jens V. Stein ◽  
Antal Rot ◽  
Yi Luo ◽  
Manjunath Narasimhaswamy ◽  
Hideki Nakano ◽  
...  
Keyword(s):  
T Cells ◽  
Lymphoid Tissue ◽  
Lymphocyte Function ◽  
Luminal Surface ◽  
High Endothelial Venules ◽  
Secondary Lymphoid Tissue ◽  
Cell Homing ◽  
Peripheral Lymph ◽  
T Cell Homing ◽  
Afferent Lymph

T cell homing to peripheral lymph nodes (PLNs) is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial tethering and rolling via L-selectin, firm adhesion of T cells requires rapid upregulation of lymphocyte function–associated antigen 1 (LFA-1) adhesiveness by a previously unknown pathway that activates a Gαi-linked receptor. Here, we used intravital microscopy of murine PLNs to study the role of thymus-derived chemotactic agent (TCA)-4 (secondary lymphoid tissue chemokine, 6Ckine, Exodus-2) in homing of adoptively transferred T cells from T-GFP mice, a transgenic strain that expresses green fluorescent protein (GFP) selectively in naive T lymphocytes (TGFP cells). TCA-4 was constitutively presented on the luminal surface of HEVs, where it was required for LFA-1 activation on rolling TGFP cells. Desensitization of the TCA-4 receptor, CC chemokine receptor 7 (CCR7), blocked TGFP cell adherence in wild-type HEVs, whereas desensitization to stromal cell–derived factor (SDF)-1α (the ligand for CXC chemokine receptor 4 [CXCR4]) did not affect TGFP cell behavior. TCA-4 protein was not detected on the luminal surface of PLN HEVs in plt/plt mice, which have a congenital defect in T cell homing to PLNs. Accordingly, TGFP cells rolled but did not arrest in plt/plt HEVs. When TCA-4 was injected intracutaneously into plt/plt mice, the chemokine entered afferent lymph vessels and accumulated in draining PLNs. 2 h after intracutaneous injection, luminal presentation of TCA-4 was detectable in a subset of HEVs, and LFA-1–mediated TGFP cell adhesion was restored in these vessels. We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs. This study also highlights a hitherto undocumented role for chemokines contained in afferent lymph, which may modulate leukocyte recruitment in draining PLNs.

scholarly journals Development of Mucosal PNAd+ and MAdCAM-1+ Venules during Disease Course in Ulcerative Colitis

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 891
Author(s):  
Britt Roosenboom ◽  
Ellen G. van Lochem ◽  
Jos Meijer ◽  
Carolijn Smids ◽  
Stefan Nierkens ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Disease Activity ◽  
High Endothelial Venules ◽  
Cell Homing ◽  
Colonic Biopsy ◽  
T Cell Homing ◽  
N 93 ◽  
Active Inflammation ◽  
Active Disease

PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd+ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1+ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd+HEVs in UC at diagnosis was 4.9% (IQR 2.0%–8.3%), while none were detected in HC. During follow-up, PNAd+HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1+venules in UC at baseline was 5.8% (IQR 2.6–10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4–10.9), p = 0.001) in active disease. In conclusion, PNAd+HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1+venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.

scholarly journals Chemokine Requirements for B Cell Entry to Lymph Nodes and Peyer's Patches

2002 ◽  
Vol 196 (1) ◽  
pp. 65-75 ◽  
Author(s):  
Takaharu Okada ◽  
Vu N. Ngo ◽  
Eric H. Ekland ◽  
Reinhold Förster ◽  
Martin Lipp ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
B Cell ◽  
Chemokine Receptor ◽  
Cell Entry ◽  
Peyer's Patches ◽  
Peyer’S Patches ◽  
Wild Type ◽  
High Endothelial Venules ◽  
Cell Homing ◽  
T Cell Homing

B cell entry to lymph nodes and Peyer's patches depends on chemokine receptor signaling, but the principal chemokine involved has not been defined. Here we show that the homing of CXCR4−/− B cells is suppressed in CCL19 (ELC)- and CCL21 (SLC)-deficient paucity of lymph node T cells mice, but not in wild-type mice. We also find that CXCR4 can contribute to T cell homing. Using intravital microscopy, we find that B cell adhesion to high endothelial venules (HEVs) is disrupted when CCR7 and CXCR4 are predesensitized. In Peyer's patches, B cell entry is dependent on CXCR5 in addition to CCR7/CXCR4. CXCL12 (SDF1) is displayed broadly on HEVs, whereas CXCL13 (BLC) is found selectively on Peyer's patch follicular HEVs. These findings establish the principal chemokine and chemokine receptor requirements for B cell entry to lymph nodes and Peyer's patches.

scholarly journals Podocalyxin-like protein is an E-/L-selectin ligand on colon carcinoma cells: comparative biochemical properties of selectin ligands in host and tumor cells

2009 ◽  
Vol 296 (3) ◽  
pp. C505-C513 ◽  
Author(s):  
Susan N. Thomas ◽  
Ronald L. Schnaar ◽  
Konstantinos Konstantopoulos
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Colon Carcinoma ◽  
Carcinoma Cells ◽  
Host Cells ◽  
High Endothelial Venules ◽  
Colon Carcinoma Cells ◽  
Selectin Ligands ◽  
Selectin Ligand ◽  
Selectin Binding

Selectins facilitate metastasis and tumor cell arrest in the microvasculature by mediating binding of selectin-expressing host cells to ligands on tumor cells. We recently identified CD44 variant isoforms as functional P-, but not E-/L-, selectin ligands on colon carcinoma cells. Furthermore, a ∼180-kDa sialofucosylated glycoprotein(s) mediated selectin binding in CD44-knockdown cells. Using immunoaffinity chromatography and tandem mass spectrometry, we identify podocalyxin-like protein (PCLP) as an alternative selectin ligand. Blot rolling and cell-free flow-based adhesion assays disclose that PCLP on LS174T colon carcinoma cells possesses E-/L-, but not P-, selectin binding activity. The selectin-binding determinants on LS174T PCLP are non-MECA-79-reactive sialofucosylated structures displayed on O-linked glycans, distinct from the MECA-79-reactive O-glycans on PCLP expressed by high endothelial venules, which is an L-selectin ligand. PCLP on CD44-knockdown LS174T cells exhibits higher HECA-452 immunoreactivity than PCLP on wild-type cells, suggesting that PCLP functions as an alternative acceptor for selectin-binding glycans. The enhanced expression of HECA-452 reactivity on PCLP from CD44-knockdown cells correlates with the increased avidity of PCLP for E- but not L-selectin. The novel finding that PCLP is an E-/L-selectin ligand on carcinoma cells offers a unifying perspective on the apparent enhanced metastatic potential associated with tumor cell PCLP overexpression and the role of selectins in metastasis.

Disparate lymphoid chemokine expression in mice and men: no evidence of CCL21 synthesis by human high endothelial venules

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 444-446 ◽  
Author(s):  
Hege S. Carlsen ◽  
Guttorm Haraldsen ◽  
Per Brandtzaeg ◽  
Espen S. Baekkevold
Keyword(s):  
T Cell ◽  
Lymphoid Tissues ◽  
Human Tissues ◽  
High Endothelial Venules ◽  
Chemokine Production ◽  
Cell Homing ◽  
Cell Recruitment ◽  
T Cell Homing ◽  
Cc Chemokine Receptor 7 ◽  
Naive T Lymphocytes

Abstract T-cell homing to secondary lymphoid tissues generally depends on chemokine-induced firm adhesion in high endothelial venules (HEVs) and is primarily mediated through the CC chemokine receptor 7 (CCR7) on lymphocytes. The CCR7 ligand designated CCL21 is considered the most important trigger because it appears constitutively expressed by murine HEVs. Surprisingly, when we analyzed human tissues, no CCL21 mRNA could be detected in HEVs. In fact, CCL21 mRNA was only expressed in extravascular T-zone cells and lymphatics, whereas immunostaining revealed CCL21 protein within HEVs. This suggests that T-cell recruitment to human lymphoid tissues depends on the transcytosis of lymphoid chemokines through HEV cells because there is at present no evidence of alternative chemokine production in these cells that could explain the attraction of naive T lymphocytes.

scholarly journals CD44 variant isoforms expressed by breast cancer cells are functional E-selectin ligands under flow conditions

2015 ◽  
Vol 308 (1) ◽  
pp. C68-C78 ◽  
Author(s):  
Venktesh S. Shirure ◽  
Tiantian Liu ◽  
Luis F. Delgadillo ◽  
Chaz M. Cuckler ◽  
David F. J. Tees ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Breast Cancer Cell Lines ◽  
Cell Phenotype ◽  
Flow Conditions ◽  
Antigen Capture ◽  
Selectin Ligands ◽  
Selectin Ligand ◽  
Ligand Activity

Adhesion of circulating tumor cells to vascular endothelium is mediated by specialized molecules that are functional under shear forces exerted by hematogenous flow. Endothelial E-selectin binding to glycoforms of CD44 mediates shear-resistant cell adhesion in numerous physiological and pathological conditions. However, this pathway is poorly understood in breast cancer and is the focus of the present investigation. All breast cancer cell lines used in this study strongly expressed CD44. In particular, BT-20 cells expressed CD44s and multiple CD44v isoforms, whereas MDA-MB-231 cells predominantly expressed CD44s but weakly expressed CD44v isoforms. CD44 expressed by BT-20, but not MDA-MB-231, cells possessed E-selectin ligand activity as detected by Western blotting and antigen capture assays. Importantly, CD44 expressed by intact BT-20 cells were functional E-selectin ligands, regulating cell rolling and adhesion under physiological flow conditions, as found by shRNA-targeted silencing of CD44. Antigen capture assays strongly suggest greater shear-resistant E-selectin ligand activity of BT-20 cell CD44v isoforms than CD44s. Surprisingly, CD44 was not recognized by the HECA-452 MAb, which detects sialofucosylated epitopes traditionally expressed by selectin ligands, suggesting that BT-20 cells express a novel glycoform of CD44v as an E-selectin ligand. The activity of this glycoform was predominantly attributed to N-linked glycans. Furthermore, expression of CD44v as an E-selectin ligand correlated with high levels of fucosyltransferase-3 and -6 and epithelial, rather than mesenchymal, cell phenotype. Together, these data demonstrate that expression of CD44 as a functional E-selectin ligand may be important in breast cancer metastasis.

scholarly journals The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell–expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches

Blood ◽  
2005 ◽  
Vol 106 (4) ◽  
pp. 1314-1322 ◽  
Author(s):  
Cornelia Halin ◽  
M. Lucila Scimone ◽  
Roberto Bonasio ◽  
Jean-Marc Gauguet ◽  
Thorsten R. Mempel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymph Nodes ◽  
Integrin Activation ◽  
High Endothelial Venules ◽  
Peripheral Lymph ◽  
Sphingosine 1 Phosphate ◽  
T Cell Homing ◽  
Prolonged Retention ◽  
Lymphocyte Egress

AbstractSphingosine-1-phosphate (S1P) and its receptor S1P1 control T-cell egress from thymus and secondary lymphoid organs (SLOs). To further define the role of S1P1 in lymphocyte trafficking, we performed adoptive transfer experiments and intravital microscopy (IVM) using both S1P1–/– lymphocytes and recipient wild-type (WT) mice treated with FTY720, an immunosuppressant that downmodulates S1P receptors. S1P1 deficiency and FTY720 caused rapid disappearance of T cells from blood, prolonged retention in SLOs, and accumulation in bone marrow, but did not alter interstitial T-cell motility in peripheral lymph nodes (PLNs) as assessed by multiphoton IVM. However, S1P1–/– lymphocytes displayed reduced short-term homing to PLNs due to attenuated integrin-mediated firm arrest in high endothelial venules (HEVs). By contrast, S1P1–/– T cells homed normally to Peyer patches (PPs), whereas S1P1–/– B cells had a marked defect in homing to PPs and arrested poorly in PP HEVs. Therefore, S1P1 not only controls lymphocyte egress from SLOs, but also facilitates in a tissue- and subset-specific fashion integrin activation during homing. Interestingly, FTY720 treatment enhanced accumulation of both S1P1 sufficient and S1P1–/– T cells in PPs by enhancing integrin-mediated arrest in HEVs. Thus, FTY720 exerts unique effects on T-cell traffic in PPs that are independent of T-cell–expressed S1P1.

scholarly journals Exosomal regulation of lymphocyte homing to the gut

2018 ◽  
Vol 3 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Eun Jeong Park ◽  
Onmanee Prajuabjinda ◽  
Zay Yar Soe ◽  
Samuel Darkwah ◽  
Michael G. Appiah ◽  
...  
Keyword(s):  
T Cells ◽  
Small Intestine ◽  
T Cell ◽  
Dependent Manner ◽  
Lymphocyte Homing ◽  
High Endothelial Venules ◽  
Cell Homing ◽  
Cell Functions ◽  
T Cell Homing ◽  
Profiling Analysis

AbstractExosomes secreted from T cells have been shown to affect dendritic cells, cancer cells, and other T cells. However, little is known about how T-cell exosomes (T exosomes) modulate endothelial cell functions in the context of tissue-specific homing. Here, we study the roles of T exosomes in the regulation of gut-specific T-cell homing. The gut-tropic T cells induced by retinoic acid secrete the exosomes that upregulate integrin α4β7 binding to the MAdCAM-1 expressed on high endothelial venules in the gut. T exosomes were preferentially distributed to the villi of the small intestine in an α4β7-dependent manner. Exosomes from gut-tropic T cells suppressed the expression of MAdCAM-1 in the small intestine, thereby inhibiting T-cell homing to the gut. Moreover, microRNA (miRNA) profiling analysis has shown that exosomes from gut-tropic T cells were enriched with miRNAs targeting NKX2.3, a transcription factor critical to MAdCAM-1 expression. Taken together, our study proposes that α4β7-expressing T exosomes distribute themselves to the small intestine and modify the expression of microenvironmental tissues such that any subsequent lymphocyte homing is precluded. This may represent a novel mechanism by which excessive lymphocyte homing to the intestinal tissues is downsized.

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