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(American Journal of Pathology. 1999;155:1013-1020.)
© 1999 American Society for Investigative Pathology

Commentary

Endothelial Ligands for L-Selectin

From Lymphocyte Recirculation to Allograft Rejection

From the Department of Anatomy, Program in Immunology, and Cardiovascular Research Institute, University of California, San Francisco, California

The article by Toppila et al¹ in this issue of The American Journal of Pathology raises the provocative possibility that the adhesion molecule L-selectin may play a significant role in the recruitment of lymphocytes to human heart allografts during rejection. The case made by these authors relies strongly on current knowledge about the high-endothelial-venule-expressed ligands (HEV ligands) for L-selectin, which participate in the constitutive homing of lymphocytes to secondary lymphoid organs. The purpose of this Commentary is to summarize and update this rapidly evolving field.

L-Selectin and its HEV-Ligands in Normal Lymphocyte Recirculation

L-selectin is broadly distributed on leukocytes in the blood. Extensive studies have established its participation in many instances of leukocyte-endothelial cell and leukocyte-leukocyte interactions.^2-6 The first established function for L-selectin was as a lymphocyte homing receptor mediating the interaction of blood-borne lymphocytes with the plump endothelial cells of HEV within peripheral lymph nodes.^7-9 As a critical step in the constitutive process of lymphocyte recirculation, this adhesive interaction initiates the recruitment of blood-borne lymphocytes into lymph nodes, where sensitization to sequestered antigens may occur. Recruitment of lymphocytes across HEV occurs as a result of a complex cascade of adhesion and signaling steps^10,11 in which L-selectin mediates the initial tethering and rolling of lymphocytes along the specialized high endothelial cells (HEC) of HEV.¹² Subsequently, chemokines such as secondary lymphoid tissue chemokine (SLC),¹³ perhaps acting in concert with signals transduced through L-selectin,¹⁴ rapidly trigger activation of LFA-1 (Lß2) on the lymphocytes.¹² The lymphocytes arrest on the endothelium and finally migrate across the HEV to complete the recruitment cascade.

In the past several years, a great deal of attention has been devoted to the molecular identification of the HEV-expressed counterreceptors (usually termed ligands) for L-selectin. Consistent with the presence of a C-type lectin domain at the amino terminus of L-selectin, all of the ligands identified to date contain carbohydrate-based recognition determinants (see next section). In mouse lymph nodes, two such ligands have been identified as GlyCAM-1¹⁵ and CD34,¹⁶ both of which are sialomucins. CD34 is a type I transmembrane glycoprotein, whereas GlyCAM-1 is a secreted molecule that lacks a transmembrane domain. Additionally, MAdCAM-1, which contains a mucin domain in addition to Ig-like domains, can function as a ligand for L-selectin in HEV of mesenteric lymph nodes and Peyer's patches.^17,18 In human, four glyco- protein ligands have been identified at the biochemical level,^19,20 two of which have been molecularly defined as CD34²⁰ and podocalyxin.²¹ As in the mouse, all of the these molecules are sialomucin-like in character.²⁰ Interestingly, CD34 and podocalyxin share the same overall structural organization (Figure 1) , with considerable sequence homology in their cytoplasmic domains.²¹ An important feature shared by these ligands is that only certain glycoforms are reactive with L-selectin. In the cases of GlyCAM-1, MAdCAM-1, CD34, and podocalyxin, naturally occurring forms exist that lack the necessary posttranslational modifications for L-selectin binding.^17,20-22 Thus, for example, although CD34 and podocalyxin are widely distributed on vascular endothelium, a limited number of vessels (eg, HEV) express glycoforms that are L-selectin reactive.^21,23 A similar dichotomy exists for PSGL-1, a major leukocyte ligand for P- and L-selectin.²⁴

View larger version (35K): [in this window] [in a new window]   Figure 1. Model of lymph node HEV ligands for L-selectin. Four sialomucins are shown. GlyCAM-1, CD34, and Sgp200 have been identified in mouse lymph node. CD34, podocalyxin, and Sgp200 have been identified in human tonsils. All of these components are recognized by MECA-79. The complex, defined by purification with MECA-79, is referred as the peripheral node addressin (PNAd). The cDNA encoding Sgp200 (sulfated glycoprotein of 200 kd) has not been cloned as yet. The white circles denote the posttranslational modifications of these ligands including sialylation, fucosylation, and sulfation. CD34 and podocalyxin share the same overall structural organization, each having an amino-terminal mucin domain, a presumed globular domain with cysteines, a transmembrane domain, and a cytoplasmic tail. There is significant sequence homology in the cytoplasmic tails.

A large number of parallels (Table 1) strongly argues that the HEV-associated, L-selectin-reactive components identified in lymph nodes constitute physiological ligands in lymphocyte homing. However, definitive proof of this function has not been achieved. In the case of Peyer's patch homing, antibody blockade experiments performed in vivo suggest that MAdCAM-1 is an important L-selectin ligand.³¹ With respect to lymph node homing, null mice have been generated for GlyCAM-1³² and CD34³³ with no obvious consequences for lymphocyte interactions with HEV. Whether there is compensation in these mutant mice or whether one of the other ligand candidates or a complex of the molecules constitutes the physiological ligands in lymph node HEV is not clear at present.

Consistent with the function of L-selectin as a lectin-like receptor, its HEV ligands require carbohydrate-based posttranslational modifications for recognition. These requirements include sialylation, fucosylation, and carbohydrate sulfation.^25,27,34-37 A detailed structural analysis of the O-linked chains of mouse GlyCAM-1 attempted to rationalize these requirements in terms of actual oligosaccharide structures.^38-40 Two sulfation modifications were detected at equal levels: sulfation at C-6 of Gal and sulfation at C-6 of GlcNAc. These modifications were found, respectively, within two capping structures, 6'-sulfo sLe^x and 6-sulfo sLe^x (Table 2) , but also occur in other structures. In the simplest O-linked chains (heptasaccharide), these capping groups branch from an internal trisaccharide known as core 2 (Table 2 , Figure 2 ). The monosulfated heptasaccharide chains represent less than 25% of the O-linked oligosaccharides of GlyCAM-1. The remaining chains, whose structures have not been solved, are more complex, with additional monosaccharides and/or multiple sulfation modifications per chain.

View larger version (30K): [in this window] [in a new window]   Figure 2. Sulfated O-linked chains of GlyCAM-1. Oligosaccharides bearing the 6'-sulfo sLex and 6-sulfo sLex tetrasaccharide capping groups (Table 2) are shown. They extend from the core 2 branch, indicated by a box. The monosulfated heptasaccharide structures, which occur in equal amounts, represent <25% of the O-linked chains in GlyCAM-1. The other structures, which have not been defined, are more complex. Some of these are larger than heptasaccharides and at least half contain more than one sulfate modification per chain. Among the more complex chains, the 6',6-disulfo sLex capping group is a candidate structure but has not yet been demonstrated.

It should also be noted that L-selectin binds to sLe^x or its sulfated derivatives with relatively low affinity.⁴³ However, it is strongly suspected that the overall affinity of ligand binding to L-selectin is greatly amplified through the multivalent presentation of oligosaccharide determinants in a mucin domain.⁴⁸ Consistent with this view, Toppila et al⁴⁹ found that a tetravalent form of sLe^x is much more potent than monovalent sLe^x as an inhibitor of L-selectin-dependent adhesion of lymphocytes to HEV.

A series of mAbs have provided additional information on relevant carbohydrate epitopes in HEV of human lymphoid organs. Thus, in agreement with the structural analysis of GlyCAM-1, several mAbs with specificity for sLe^x-related structures stain HEV.^29,46,50-52 Two of these (2F3 and HECA-452) were used in the study by Toppila et al.¹ Some of the sLe^x-reactive antibodies are capable of blocking in vitro attachment of lymphocytes to HEV; others are not.^29,50,52 Recently, two additional antibodies were described, G72 and G152, that recognize 6-sulfo sLe^x, one of the capping groups in GlyCAM-1.⁴⁶ Importantly, these antibodies strongly stain HEV in human lymph nodes and tonsils and block staining of lymph node HEV with an L-selectin/IgG chimera. With respect to the 6'-sulfo sLe^x and 6',6-disulfo sLe^x structures, a series of antibodies that react with chemically synthesized versions of these structures fail to stain HEV in human lymphoid organs.⁴⁶

Another mAb used by Toppila et al¹ is MECA-79, which, as reviewed above, has been useful for the biochemical identification of ligand molecules. One of the remarkable features of this mAb, in contrast to the others, is that it reacts with HEV across a wide wide range of species including mouse and human.⁵³ Structural characterization of the MECA-79 epitope, although incomplete at the present time, has established that it depends on sulfation,²⁷ in particular the GlcNAc-6-sulfate modification⁵⁴ (see next section). In contrast to the sLe^x-reactive mAbs, the MECA-79 epitope is independent of sialylation and fucosylation.^27,35 Another series of mAbs, the JG series, was recently prepared against the MECA-79-reactive complex of glycoproteins isolated from human tonsils (PNAd).⁵⁵ These antibodies stain HEV in various organs, and some are function-blocking. Other than their sialic acid dependency, the epitopes of the JG antibodies are not structurally defined.

An intriguing feature of the aforementioned antibodies is the varied staining of HEV in different lymphoid organs.^28,46,55 For example, although mouse Peyer's patch HEV clearly express functional apical ligands for L-selectin,¹⁸ staining of these vessels with MECA-79 is very weak and the reactivity is mostly ablumenal.²⁶ In human, G72 and G152 reactivity of tonsillar and lymph node HEV is much stronger than that of appendix HEV.⁴⁶ Similar heterogeneity is observed for the JG antibodies.⁵⁵ These immunohistochemical findings indicate significant diversity in the carbohydrate-based epitopes expressed by different HEV.

Enzymes Involved in the Elaboration of Fucosylation and Sulfation Modifications of HEV-Ligands for L-Selectin

As reviewed in Toppila et al,¹ fucosyltransferase VII (FTVII), an 1,3 fucosyltransferase, has been directly implicated in the synthesis of the sLe^x-related ligands in lymphoid organs of mouse. With respect to the carbohydrate sulfation of the ligands, the two relevant activities are GlcNAc-6-O- and Gal-6-O sulfotransferases. Three recently cloned enzymes with these specificities^56-61 and belonging to the GST subfamily of carbohydrate sulfotransferases⁶² have been implicated in L-selectin ligand biosynthesis (Table 3) . mRNA corresponding to each of these enzymes has been detected in lymph node and tonsillar HEV by in situ hybridization or reverse transcriptase-polymerase chain reaction.^58,60,61 However, whereas the expression of HEC-GlcNAc6ST,⁶⁰ also termed L-selectin ligand sulfotransferase (LSST),⁶¹ is highly restricted to HEV, the other two enzymes are widely distributed. It is likely that HEC-GlcNAc6ST/LSST is responsible for the GlcNAc-6-O sulfotransferase activity, which has been shown to be highly enriched in isolated HEC from porcine lymph nodes.⁶³ All three of the cloned enzymes are capable of making the appropriate sulfation modification (Gal 6-sulfate or GlcNAc 6-sulfate) on actual L-selectin ligands (eg, GlyCAM-1, CD34, and MAdCAM-1) in transfected cells.^60,61,64 Transfection of a cDNA for either of the two GlcNAc-6-O-sulfotransferases in combination with a FTVII cDNA leads to the elaboration of the 6-sulfo sLe^x epitope on the surface of transfected cells, as defined by the G72/G152 mAbs.^54,60 These results establish that one of the key sulfated structures found in GlyCAM-1 and known to be present on HEV in human lymphoid organs can be generated by the two enzymes. In addition, stable transfection of the GlcNAc6ST cDNA (Table 2) into ECV304 cells (human bladder cancer cells) results in the generation of the MECA-79 epitope, thus establishing that the GlcNAc-6-sulfate modification is required for this structure.⁵⁴

L-Selectin Ligands Induced on Endothelium at Sites of Chronic Inflammation

HEV-like vessels, possessing plump endothelial cells and other morphological features of HEV in secondary lymphoid organs, are induced in many settings of chronic inflammation.⁶⁵ These vessels occur in association with perivascular lymphocytes^66,67 and can support in vitro lymphocyte attachment.^68-71 Therefore, by analogy with the function of HEV in lymphoid organs, it is inferred that HEV-like vessels serve as a major portal of lymphocyte emigration from the blood into chronically inflamed tissues. Extensive studies performed in human and various animal models have demonstrated MECA-79 staining of HEV-like vessels in many examples of chronic inflammation (Table 4) . In human, a wide variety of cutaneous lesions exhibit such staining.^67,71 In several instances, staining with HECA 452^50,72,73 or in vitro incorporation of ³⁵SO₄^68,74 have been demonstrated for HEV-like vessels. Taken together, this evidence is strongly suggestive of the presence of L-selectin ligands. In a few cases, direct evidence for these ligands is available through either in vitro adhesion assays in which an L-selectin mAb is used to inhibit lymphocyte attachment to the HEV-like vessels.^69-71 or direct staining of the HEV-like vessels with an L-selectin/IgG chimera.⁷⁵ For example, AKR mice exhibit a hyperplastic thymus which is associated with the presence of MECA-79+ HEV-like vessels in the medulla.⁷⁰ The MEL-14 mAb (anti-mouse L-selectin) and MECA-79 block in vitro lymphocyte attachment to these vessels by 68% and 60%, respectively. The residual adhesion in this system appears to be due largely the 4ß7-MAdCAM-1 interaction. At cutaneous sites of inflammation, The VAP-1 system appears to complement the L-selectin system, with the latter responsible for about 60% of PBL adhesion, as judged by MECA-79 inhibition.⁷¹ In vivo confirmation that L-selectin is indeed a significant contributor to trafficking through HEV-like vessels is thus far available only in the AKR hyperplastic thymus model.⁷⁰ Injection of these animals with MEL-14 or with MECA-79 substantially decreases (70–80%) lymphocyte migration to the thymus.

A hallmark of organ transplant rejection is the influx of lymphocytes into the graft.⁷⁶ Therefore, blocking lymphocyte recruitment is a promising approach for preventing rejection, thus motivating investigation of the molecular mechanisms of lymphocyte trafficking in these systems. A pivotal study from the laboratory of R. Renkonen⁷⁷ provided the foundation for the present report by Toppila et al¹ in this issue of the Journal. Using a rat model of acute cardiac allograft rejection, these investigators demonstrated the induction of L-selectin ligands on flat-walled venules and capillaries within rejecting cardiac allografts. These vessels, defined by staining with sLe^x-related antibodies and an L-selectin/IgG chimera, support L-selectin-dependent binding of lymphocytes in an vitro adhesion assay. Transplantation studies in other animal models have also implicated the L-selectin pathway in lymphocyte recruitment and graft rejection.^78,79

Guided by these results, Toppila et al¹ have now addressed the question of whether L-selectin ligands are induced on vascular endothelium during rejection of human cardiac allografts. The approach was strictly histochemical, employing three mAbs (2F3, HECA-452, and MECA-79) that have been used to study L-selectin ligands in other systems. HECA-452 and 2F3 recognize sLe^x-related structures. HECA 452 does not block lymphocyte attachment to HEV.⁵⁰ Interestingly, it is inhibitory when tested on L-selectin ligands that are induced on TNF--treated HUVEC.⁸⁰ As reviewed above, MECA-79 recognizes a GlcNAc-6 sulfate-dependent within L-selectin ligands and is function-blocking, although its activity is varied at different anatomical sites.^67,81

Applying these reagents to endomyocardial biopsies taken from heart allografts, Toppila et al¹ observed a striking induction of these epitopes on intramuscular capillaries and venules in those individuals exhibiting histological signs of acute rejection. A correlation was established between the staining intensity on vessels (as well as the number of biopsies showing positive staining) and the severity of acute rejection. Moreover, in serial samples taken from three patients experiencing rejection, staining of vessels increased with rejection and subsided when immunosuppression therapy ameliorated the rejection episode. The availability of an antibody to FTVII allowed the investigators to demonstrate expression of this enzyme in activated vessels of the grafts, again in correspondence with histological parameters of rejection. This enzyme is likely to be pivotal in the synthesis of the sLe^x-related epitopes that were observed on the activated vessels.

Two distinguishing features of this study, in comparison to the anecdotal nature of previous investigations of inflammatory lesions in human patients, are that a large number of samples were analyzed (600 endomyocardial biopsies, of which 91 showed signs of acute rejection) and the analysis was quantitative. Hence, the conclusions that were reached are supported by statistical tests.

A number of important issues remain to be addressed. As reviewed above, staining with the indicated mAbs is strongly predictive of L-selectin ligand activity. However, confirmation of this activity will require in vitro adhesion assays or staining with a soluble recombinant form of L-selectin. Use of mAbs in the adhesion assays will allow assessment of the possible contribution of adhesion pathways (P-selectin, E-selectin, VAP-1, 4ß7, 4ß1, etc.) other than the L-selectin pathway. Because histochemical staining with L-selectin/IgG chimeras has been limited by weak signals,⁷⁵ the use of high avidity IgM chimeras of L-selectin^35,60,82 is likely to be beneficial. Alternatively, mild-periodate oxidation of tissue sections might be used to enhance staining reactions,⁸³ assuming that the L-selectin ligands are sialic acid-dependent.

The identity of the macromolecular ligands (CD34, podocalyxin, Sgp200, MAdCAM-1, or perhaps a unique protein scaffold) that are induced on the activated endomyocardial vessels remains to be determined. Without specific reagents that are function-blocking for individual components, it will be difficult to parse functions among what is likely to be a multiplicity of ligand candidates.

It is, however, presently feasible to obtain additional information about the potential sulfation modifications of the ligands expressed in the allografts. Although staining with MECA-79 suggests the presence of the GlcNAc-6-sulfate moieties, the newly described G72 and G152 mAbs are better characterized reagents with demonstrated specificity for 6-sulfo sLe^x. As reviewed above, this structure is a clearly validated recognition determinant for L-selectin (Table 1) . Staining of the allograft samples with these antibodies, in conjunction with in situ hybridization assays for GlcNAc-6-O sulfotransferase transcripts (Table 3) , could be very illuminating. In this regard, it is noteworthy that Hiraoka et al⁶¹ recently reported the induction of HEC-GlcNAc6ST/LSST transcripts in HEV-like vessels in the hyperplastic thymus of AKR mice. The presence of Gal-6-O sulfotransferases (eg, KSGal6ST) in vessels of the allografts should also be explored, as the modification conferred by this class of enzyme also enhances L-selectin ligand activity.⁶⁰ It has been suggested⁶⁰ that heterogeneity in L-selectin ligands within different vascular beds may be based on differential expression of the different classes of sulfotransferases.

As reviewed by Toppila et al,¹ a number of molecules other than L-selectin have been implicated in lymphocyte recruitment to rejecting allografts. In principle, components could act at later steps in an L-selectin-initiated cascade. Alternatively, other components could contribute to L-selectin-independent cascades. The example set by Toppila and coworkers provides a paradigm for the evaluation of other candidate molecules on a rigorous basis. Studies of this type may identify therapeutic targets for novel treatments of allograft rejection.

Acknowledgements

I want to express my gratitude to Annette Bistrup, Richard Bruehl, Stefan Hemmerich, Chris Sassetti, Mark Singer, and Kirsten Tangemann for their helpful comments on this manuscript.

Footnotes

Address reprint requests to Steven D. Rosen, Department of Anatomy, University of California, San Francisco, CA 94143-0452. E-mail: sdr{at}itsa.ucsf.edu

Supported by grants from the National Institutes of Health (R37GM23547 and RO1GM5741) and Roche Bioscience.

Accepted for publication August 18, 1999.

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