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1 Integrin-Mediated Adhesion by Yoshiya Tanaka,* Steven M

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1 Integrin-Mediated Adhesion by Yoshiya Tanaka,* Steven M CD31 Expressed on Distinctive T Cell Subsets Is a Preferential Amplifier of/~1 Integrin-mediated Adhesion By Yoshiya Tanaka,* Steven M. Albelda,Ig Kevin J. Horgan,* G13s ~ A. van Seventer,* Yojl.~ Shlmzzu, II Walter Newman, ~'- John Hallam,* Peter J. Newman,** Clayton A. Buck,$ and Stephen Shaw* From *The Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; the IPulmonary and Critical Care Section, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104; SThe Wistar Institute, Philadelphia, Pennsylvania 19104; the IIDepartmentof Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan 48109; the IDepartment of Endothelial Cell Biology, Otsuka America Pharmaceutical, Ina, Rockville, Maryland 20850; and the **BloodResearch Institute, Tile Blood Center of Southeastern Wisconsin, Milwaukee, Wisconsin 53233 SummAry 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 ceUs and thereby function in immunity, inflammation, and wound healing. We report the following novel features of CD31 which suggest a role for it in adhesion amplification of unique T cell subsets: (a) engagement of CD31 induces the adhesive function of/31 and/~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 fll integrins, particularly very late antigen-4, more efhciently than the f12 integrin lymphocyte function-associated antigen-1. Conversely, CD3 is more effective in inducing ~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 calls. gulated adhesion is critical to virtually all the functions grins and L-sdectin (LAM-1/Leu-8); regulated expression of l~ oft lymphocytes. These functions inchde both antigen- the ligands such as intracellular adhesion molectde-1 (ICAM-1), independent processes such as lymphocyte recircnlation/ vascular cell adhesion molecnle-1 (VCAM-1), and E-sdectin homing and antigen-specificrecognition events. Consequently, (endothelial leukocyte adhesion molecule-1 [ELAM-1]); and evolution has provided multiple modes of regulation of T regulated function of the T cell adhesion receptors. cell adhesion. These include regulated expression of the T It is rapidly becoming apparent that this last mode of regu- cell adhesion receptors such as very late antigen (VLA) 1 inte- lation, namely regulated function of the adhesion receptors, is powerful and widely used, not only by T cells, but by other cell types (1-10). Regulated function is a prominent charac- teristic of the integrin adhesion molecules, which are a di- 1 Abbreviations used in thispaper: ELAM-1, endothelial leukocyte adhesion verse family of heterodimeric adhesion receptors used by vir- molecule-I; FN, fibronectin; HEV, high endothelial venule; HSA, human serum albumin; ICAM-1, intracetlular adhesion molecule-I; LN, laminin; tually all cell types in adhesion to other cells and to extracellular PECAM-1, platelet endothelial cell adhesion molecule-I; VCAM-1, vascular matrix (11-14). Resting T calls express at least five integrins cell adhesion molecule-I; VLA, very late antigen. (11, 15). LFA-1 (c~LB2), the best known integrin on resting 245 The Journal of Experimental Medicine Volume 176 July 1992 245-253 T cells, mediates primarily cell-cell interactions via at least tive immunomagnetic negative selection, essentially as previously three distinct ligands: ICAM-1, ICAM-2, and ICAM-3 (12, described (27). We routinely use Advanced Magnetic Particles (Ad- 16). In addition, there are four ~1 integrins (VLA-3, VLA-4, vanced Magnetics, Cambridge, MA) and/or Dynabeads (DynalInc., VLA-5, and VLA-6) that mediate adhesion both to extracel- Fort Lee, NJ), and a cocktail of mAbs consisting of MHC class lular matrix via fibronectin (FN) and laminin (LN) (15) and II mAb IVA12, CD19 mAb FMC63, CD16 mAb VD2, CD11b to other cells via VCAM-1 (17). It is remarkable that inte- mAb NIHllb-1, CD14 mAb 63D3, antiglycophorin mAb 10F7, and CD4 mAb OKT4 or CD8 mAb B9.8.4 with or without grins on circulating ("resting") T cells do not mediate effec- CD45RA mAb FMC71 (to negatively isolate memory T cells), tive adhesion. Dustin and Springer (1) demonstrated that cross- or CD45RO mAb UCHL1 (to negatively isolate naive T cells) linking of the CD3/TCR complex induces transient adhesion (27). The anti-HLA-DK mAb IVA12 was included in the selec- via LFA-1, and proposed that such regulated adhesion could tion cocktail to exclude the normal low percentage of circulating account for many of the adhesive events that accompany activated T cells. Furthermore, the CD8 dull (dim) population which antigen-specific T cell recognition. Thereafter, the concept has YK-like features phenotypically and functionally (28), was also of regulated integrin function on T cells has been general- excluded from the CD8 § population by the use of a separation ized by extensions in a variety of directions: (a) the ~1 inte- cocktail containing the CD16 mAb VD2 and the CD11b mAb grins show similar regulated function on resting T cells (15); NIHllb-1. The purity of T cell subsets were >96% CD4 § or (b) antigen-specific recognition induces ~1 integrin function >94% CD8 +, and >99% CD45R.A + or >99% CD45RO § as determined by flow cytometric analysis. on T cells (18); and (c) integrin function on T cells is regu- Antibodies and other Reagents. The following mAbs were used lated not only by CD3 crosslinking (and the similar activa- as purified Ig: CD31-specific mAb NIH31-1 and NIH31-2 were tion stimulus provided by pairs of CD2 mAb), but also by generated and their specificity documented by binding to CD31- crosslinking of other receptors on the T cell surface, including transfectants (data not shown); CD31 mAb PECAM-1.2 (P. J. CD7, CD28, and CD44 (1, 15, 19, 20). These findings for Newman, unpublished observations), CD31 mAb 4G6 (S. M. A1- T cells have been both foreshadowed and complemented by belch, unpublished observations), CD31 mAb SG134 (29) (S. Goyert, a variety of findings regarding regulated function of integrins CorneU University Medical College, Manhasset, NY), CD31 mAb on other cell types including particularly platelets, granulo- LAK1 (30) (M. Zocchi, Laboratory of Adoptive Immunotherapy, cytes, and B cells (3-7, 10). Milan, Italy), CD31 mAb L33 (D. Buck; Becton Dickinson & Co., We use the terms adhesion "inducer" or "amplifier" to refer San Jose, CA). Other mAb are as follows: CD11b mAb NIH11b-1, CD49d mAb NIH49d-1, CD44 mAb NIH44-1 (31) and CD45 to a molecule on the T cell surface that augments integrin mAb NIH45-2 (generated locally), CD3 mAb OKT3, CD4 mAb function. The nature of regulated adhesion makes the amplifier OKT4, CD14 mAb 63D3, class II mAb IVA12, CD7 mAb 3A1, molecules as critical to the process as the adhesion molecule antiglycophorin mAb 10F7 (all from American Type Culture Col- itself. In particular, differential expression of such amplifier lection, Kockville, MD), CD2 mAb 95-5-49 (R. K. Quinones, molecules will be as important in T cell differentiation as Children's Hospital Medical Center, Washington, DC), CD8 mAb differential expression of the adhesion molecule. The present B9.8.4 (B. Malissen, Centre National de la Recherche Scientifique, report identifies CD31 as an amplifier molecule on unique Marseilles, France), CD19 mAb FMC63, CD45RA mAb FMC71 subsets of T cells, and characterizes novel features of that adhe- (H. Zola, Flinders Medical Center, Bedford Park, Australia), sion induction. CD31 glycoprotein (also designated PECAM-1, CD45KO mAb UCHL1 (P. Beverley, Courtauld Institute of Bio- platelet endothelial cell adhesion molecule) is an Ig super- chemistry, London, UK), CD18 mAb MHM23 (J. E. Hildreth, family member that is most similar in structure to classical Johns Hopkins Medical School, Baltimore, MD). CD49d mAb L25 (D. Buck), CD29 mAb MAB13, CD49e mAb MAB16 (both K. adhesion molecules such as ICAM-1, VCAM-1, and neural Yamada, National Institute of Dental Research, Bethesda, MD), cell adhesion molecule (NCAM) (21). It is expressed at high CD28 mAb CLB-28/1 (K. van Lier, Centraal Laboratorium van density on endothelium, platelets, granulocytes, and mono- de Bloedtransfusiedienst (CLB) Amsterdam, The Netherlands), cytes (22-24). It is also expressed by lymphocytes (23, 24). CD16 mAb VD2 (A. E. G. K. von dem Borne, CLB, Amsterdam, It has been implicated in cell-cell adhesion by a variety of The Netherlands). CD31 polyclonal Ab PECAM IgG was prepared findings. It accumulates at contact regions between endothelial by Protein A affinity chromatography from polyclonal rabbit anti- cells (22), transfection of CD31 into L cells causes them to CD31 antisera (25, 32). IgG was present at 10 #g/ml final concen- aggregate (25), and CD31 mAbs inhibit endothelial cell con- tration throughout the assays, except for CD28 mAb which was tact, as well as transfected L cell aggregation (25). CD31 has used at a 1:1000 concentration which is functional in other assays. been postulated to bind to CD31 in homophilic interactions, Purified soluble VCAM-1 was prepared as previously described (33). Human FN was obtained from New York Blood Center, New as well as to participate in heterophilic interactions involving York. ICAM-1 was purified by affinity chromatography from the proteoglycans (22, 26). The present report demonstrates a Reed-Sternberg cell line L428 as previously described (34).
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