CD Antigens 2001: Aims and Results of HLDA Workshops

DAVID MASON,a PASCALE ANDRÉ,b ARMAND BENSUSSAN,c CHRIS BUCKLEY,d CURT CIVIN,e

EDWARD CLARK,f MASJA DE HAAS,g SANNA GOYERT,h MARTIN HADAM,i DEREK HART,j

VÁCLAV HOREJSÍ,k STEFAN MEUER,l JAMES MORRISSEY,m REINHARD SCHWARTZ-ALBIEZ,n

STEPHEN SHAW,o DAVID SIMMONS,p MARIAGRAZIA UGUCCIONI,q ELLEN VAN DER SCHOOT,g

ERIC VIVIER,b HEDDY ZOLAr

aThe Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, United

Kingdom; bCentre d'Immunologie, Parc Scientifique de Luminy, Cedex, France; cFaculte de Medicine de

Creteil, Cedex, France; dDivision of Immunity and Infection, MRC Center for Immune Regulation,

Department of Rheumatology, University of Birmingham, Edgbaston, Birmingham, United Kingdom;eJohns Hopkins Comprehensive Cancer Center, Baltimore, Maryland, USA; fDepartment of Microbiology,

University of Washington, Seattle, Washington, USA; gCLB, Department of Experimental

Immunohematology, Amsterdam, The Netherlands; hLaboratory of Molecular Hematology/Division

of Molecular Medicine, North Shore University Hospital, Manhasset, New York, USA; iKinderklinik,

Medizinische Hochschule Hannover, Hannover, Germany; jMater Medical Research Institute, Aubigny

Place, Mater Hospital, Queensland, Australia; kInstitute of Molecular Genetics AS CR, Prague,

Czechoslovakia; lInstitut für Immunologie der Univ. Heidelberg, Heidelberg, Germany, mProfessor of

Biochemistry, University of Illinois College of Medicine, Urbana, Illinois, USA; nGerman Cancer

Research Center, Heidelberg, Germany; oNational Institute of Health, Bethesda, Maryland, USA; pDirector of Biology Celltech R&D Ltd., Cambridge, United Kingdom; qInstitute for Research in

Biomedicine, Bellinzona, Switzerland; rUniversity of Adelaide, Department of Pediatrics, Women's

and Children's Hospital, South Australia, Australia

STEM CELLS 2001;19:556-562 www.StemCells.com

Correspondence: David Y. Mason, Ph.D., The Nuffield Department of Clinical Laboratory Sciences, University of Oxford,Oxford, United Kingdom. Telephone: 44-1865-220356; Fax: 44-1865-763272; e-mail: david.mason@ndcls.ox.ac.ukReceived June 25, 2001; accepted for publication July 30, 2001. ©AlphaMed Press 1066-5099/2001/$5.00/0

THE TRADITION OF HLDA WORKSHOPS

The process of categorizing the antigenic moleculesand epitopes associated with human white cells, via the col-laborative study of monoclonal antibodies, dates back to theearly 1980s, when the first HLDA (Human LeucocyteDifferentiation Antigen) Workshop was held in Paris. Thisinitial meeting listed only 15 agreed-upon molecular enti-ties, but it created an internationally agreed basis for thenomenclature of leucocyte molecules (the CD scheme), andalso provided a forum for reporting studies on their functionand practical relevance. A further six HLDA meetings have

been held since the first Paris meeting. The most recent ofthese (HLDA7) took place last year in Harrogate, UK, andthe proceedings of the meeting will be published later thisyear (Leucocyte Typing VII, Oxford University Press).

THE AIMS AND APPROACHES OF THE

7TH HLDA WORKSHOP

The Limitations of “Blind” Antibody ScreeningIt was apparent at the previous meeting, HLDA6, held in

Kobe, Japan in 1996, that the technique of detecting molecular

Meeting Report

Stem Cells

Mason, André, Bensussan et al. 557

Table 1. New CD designations

CD designation Name Section Locus linkCD15u Sulphated CD15 Carbohydrate structuresCD60a GD3 Carbohydrate structuresCD60b 9-O-acetyl-GD3 Carbohydrate structuresCD60c 7-O-acetyl-GD3 Carbohydrate structuresCD75 Lactosamines Carbohydrate structuresCD75s Alpha-2,6-sialylated lactosamines (formerly CDw75 and CDw76) Carbohydrate structuresCD85 ILT/LIR family (Table 2) Dendritic cellsCD110 MPL, thrombopoietin receptor (TPO R) Platelets 4352CD111 PRR1/Nectin1 Myeloid cells 5818CD112 PRR2 Myeloid cells 5819CD133 AC133 Stem/progenitor cells 8842CD156b TACE/ADAM17 Adhesion structures 6868CD158 KIR family (Table 2) NK cellsCD159a NKG2A NK cells 3821CD160 BY55 T cells 11126CD162R PEN5 NK cells 6404CD167a Discoidin domain R (DDR1) Adhesion structures 780CD168 RHAMM Adhesion structures 3161CD169 Sialoadhesin Adhesion structures 6614CD170 Siglec-5 Adhesion structures 8778CD171 L1 Adhesion structures 3897CD172a SIRP alpha Adhesion structures 8194CD173 Blood group H type 2 Carbohydrate structuresCD174 Lewis y Carbohydrate structuresCD175 Tn Carbohydrate structuresCD175s Sialyl-Tn Carbohydrate structuresCD176 TF Carbohydrate structuresCD177 NB1 Myeloid cellsCD178 Fas ligand Cytokine/chemokine receptors 356CD179a Vpre-B B cells 7441CD179b Lambda 5 B cells 3543CD180 RP105 B cells 4064CD183 CXCR3 Cytokine/chemokine receptors 2833CD184 CXCR4 Cytokine/chemokine receptors 7852CD195 CCR5 Cytokine/chemokine receptors 1234CDw197 CCR7 Cytokine/chemokine receptors 1236CD200 OX2 Nonlineage molecules 4345CD201 EPC R Endothelial cells 10544CD202b Tie2 (Tek) Endothelial cells 7010CD203c NPP3/PDNP3 Myeloid cells 5169CD204 Macrophage scavenger R Myeloid cells 4481CD205 DEC205 Dendritic cells 4065CD206 Macrophage mannose R Dendritic cells 4360CD207 Langerin Dendritic cells 50489CD208 DC-LAMP Dendritic cellsCD209 DC-SIGN Dendritic cells 30385CDw210 Interleukin-10 receptor (IL-10 R) Cytokine/chemokine receptors 3587; 3588CD212 IL-12 R Cytokine/chemokine receptors 3594CD213a1 IL-13 R alpha 1 Cytokine/chemokine receptors 3597CD213a2 IL-13 R alpha 2 Cytokine/chemokine receptors 3598CDw217 IL-17 R Cytokine/chemokine receptors 23765CD220 Insulin R Nonlineage molecules 3643CD221 Insulin growth factor receptor (IGF1 R) Nonlineage molecules 3480CD222 Mannose-6-phosphate/IGF2 R Nonlineage molecules 3482CD223 LAG-3 Nonlineage molecules 3902CD224 Gamma-glutamyl transferase Nonlineage molecules 2678CD225 Leu13 Nonlineage molecules 8519CD226 DNAM-1 (PTA1) T cells 10666CD227 MUC.1 Nonlineage molecules 4582CD228 Melanotransferrin Nonlineage molecules 4241CD229 Ly9 Nonlineage molecules 4063CD230 Prion protein Nonlineage molecules 5621

558 CD Antigens 2001

entities by screening coded panels of monoclonal antibodiesagainst human cells was becoming obsolete. Antibodies tothe most immunogenic molecules had already been pro-duced, and fewer laboratories than in the early days were pre-pared to devote resources to raising new antibodies, since theprobability of finding novel reagents becomes ever lesslikely. As a consequence many antibodies in HLDA6 werereagents (submitted by laboratories that were not equipped tocharacterize them) that proved to be of known specificity.

Selection of AntibodiesWith these considerations in mind, HLDA7 adopted a dif-

ferent approach: instead of screening poorly characterizedantibodies, reagents were selected (and actively solicited) forwhich at least some molecular data were already available. Asubstantial number of monoclonal antibodies reactive withleucocyte-associated molecules exist that do not meet the tra-ditional criteria for establishing a new CD specificity (i.e., theexistence of at least two independent antibodies of the samespecificity). This rule dates from the first HLDA Workshoptwo decades ago. Since that time biochemical and molecularbiological techniques for characterizing the targets of newantibodies have come to be widely used. Consequently, it isnow considered appropriate to establish a CD designation fora molecule if its gene has been cloned and at least one specificmonoclonal antibody has been studied in the Workshop.

New Workshop SectionsFour new Sections were introduced in HLDA7 to add to

the traditional list from past meetings: namely Dendritic

Table 1. New CD designations (continued)

CD designation Name Section Locus link

CD231 TALLA-1/A15 Nonlineage molecules 7102CD232 VESP R Nonlineage molecules 10154CD233 Band 3 Erythroid cells 6521CD234 Fy-glycoprotein (DARC) Erythroid cells 2532CD235a Glycophorin A Erythroid cells 2993CD235b Glycophorin B Erythroid cells 2994CD235ab Glycophorin A/B cross-reactive monoclonal antibodies (mAbs) Erythroid cellsCD236 Glycophorin C/D Erythroid cellsCD236R Glycophorin C Erythroid cells 2995CD238 Kell Erythroid cells 3792CD239 B-CAM Erythroid cells 4059CD240CE Rh30CE Erythroid cells 6006CD240D Rh30D Erythroid cells 6007CD240DCE Rh30D/CE cross-reactive mAbs Erythroid cellsCD241 RhAg Erythroid cells 6005CD242 ICAM-4 Erythroid cells 3386CD243 Multidrug resistant (MDR)-1 Stem/progenitor cellsCD244 2B4 NK cells 51744CD245 p220/240 T cellsCD246 Anaplastic lymphoma kinase T cells 238CD247 Zeta chain T cells 919

Table 2. New CD nomenclature for ILT/LIR and KIR molecules

CD designation Name

The ILT/LIR familyCD85a ILT5/LIR3CD85b ILT8CD85c LIR8CD85d ILT4/LIR2, MIR10CD85e ILT6/LIR4CD85f ILT11CD85g ILT7CD85h ILT1/LIR7CD85i LIR6CD85j ILT2/LIR1, MIR7CD85k ILT3/LIR5CD85l ILT9CD85m ILT10

The KIR familyCD158z KIR3DL7/KIRC1CD158b1 and CD158b2 KIR2DL2/p58.2 and KIR2DL3/p58.3CD158a KIR2DL1/p58.1CD158c KIR2DS6/KIRXCD158d KIR2DL4CD158e1 and CD158e2 KIR3DL1/p70 and KIR3DS1/p70CD158f KIR2DL5CD158g KIR2DS5CD158h KIR2DS1/p50.1CD158i KIR2DS4/p50.3CD158j KIR2DS2/p50.2CD158k KIR3DL2/p140

For further details of this classification, based on the position ofthe genes on chromosome 19q;13.4 from centromeric to telomericloci [1].

Mason, André, Bensussan et al. 559

Table 3. Examples of possible future CD specificities

Molecule Mol. Size Cell types Comments References

Identified following antibody production

AM-3K antigen 70 and 120 kDa Macrophages [2]

BDCA-2, BDCA-3, and Dendritic cells Identifies subsets of [3]BDCA-4 antigens dendritic cells.

BENE 17 kDa Endothelium “Raft-associated” member [4]of MAL family. Interacts with caveolin-1.

CMRF-44 ? Dendritic cells Differentiated/Activated [5, 6]CMRF-56 95 kDa Dendritic cells Differentiated/Activated

H47 antigen 100 kDa (non red.) T cells and most NK, ? Involved in T cell [7]120 kDa (red.) B cells, and monocytes activation

Hal-1 200 kDa (100 kDa) T cells, EBV-transformed ? New lymphoma marker [8]B-cells, myelomonocytic cells, anaplastic large cell lymphoma

LAK1 and LAK2 antigens 120 kDa and 110 + [9]140 kDa respectively LGL and LAK cells

NKp80 80 kDa dimer NK cells and CD56-positive Novel member of the killer [10, 11]T cells cell lectin-like receptor gene

family, encoded by KLRF1 gene. Triggers NK cell cytotoxicity.

VAP-1 (Vascular 90 kDa Endothelium Mediates lymphocyte- [12, 13]adhesion protein) endothelial adhesion.

Has monoamine oxidase activity.

Wue-1 antigen 94 kDa Plasma cells Stimulates growth of [14]plasma cells.

Identified via gene cloning

B cell maturation 184 aa B cells TNFR family member. [15, 16]factor (BCMA) Receptor for TALL-1 and APRIL.

B7-H2 302 aa Dendritic cells New member of B7 family. [17]Binds ICOS on activated T cells.

CLEC-1 280 aa Dendritic cells Novel C-type lectin-like [18]receptor with cytoplasmic tyrosine-based motif.

CMRF-35A 224 aa NK cells, neutrophils, monocytes, Novel Ig superfamily [19, 20]CMRF-35H 300 aa dendritic cells, and subset of receptors. CMRF-35H contains

T lymphocytes. 3 cytoplasmic tyrosine based motifs.

CS1 NK cells Novel receptor belonging to [21]CD2 subset of Ig superfamily.

DC-STAMP 470 aa Dendritic cells Novel protein containing seven [22]putative transmembrane domains.

EMR3 652 aa Mainly leucocyte restricted. Novel EGF-TM7 molecule. [23]Highest levels on neutrophils, Interacts with a surface ligand monocytes, and macrophages. on myeloid cells.

Flt-1 (VEGFR-1) Endothelial cells, monocytes [24]

GPRv53 390 aa Leukocytes Identified by gene cloning. [25]G-protein-coupled histamine receptor.

IRTA1 and IRTA2 Subpopulations of B cells Homologous to the Fc and [26]inhibitory receptor families.

560 CD Antigens 2001

Cells, Stem/Progenitor Cells, Erythroid Cells, andCarbohydrate Structures. Although it has been recognizedfor many years that monoclonal antibodies reactive withhuman leucocytes can be specific for carbohydrate epitopes(e.g. the carbohydrate CD category CD15 was identified atthe first Workshop), they had not received specific attentionin any Workshop. The inclusion of erythroid molecules,although it may seem out of place in a “LeucocyteWorkshop,” was justified by the number of moleculesshared between white and red cells (e.g., cytokine receptors)that hint at unexplored functions of red cells.

THE YIELD OF NEW CD SPECIFICITIES IN HLDA7This more active approach to the identification of new

CD specificities represented a break with tradition, but theresults justified the new approach, since a total of well over80 new entities were added to the list of CD specificities.This compares favorably with previous Workshops (anaverage of fewer than 30 CD specificities per Workshop),and it also largely avoided the laborious screening in multi-ple laboratories of antibodies that prove to be directedagainst known CD molecules.

Tables 1 and 2 list the new specificities established atHLDA7. Full details will be found in Leucocyte Typing VII,and molecular, functional, and other data can be found for manyof these new specificities on the PROW (Protein Reviews onthe Web) website (http://www.ncbi.nlm.nih. gov/prow).

THE EIGHTH WORKSHOP

Plans are well advanced for HLDA8, to be organized inAdelaide in 2004 under the aegis of Prof. H. Zola (see:www.hlda8.org). It is sometimes assumed that the catalogof surface molecules associated with human hemopoietic

cells is now essentially complete, but there is abundant evi-dence in the literature for novel surface molecules that wouldmerit study at the next Workshop, and that could provide thebasis for new CD designations. Table 3 comprises a list ofpotential new molecules reported following the production ofmonoclonal antibodies, and also a more extensive list of sur-face molecules identified via gene cloning. In most instances,no antibodies are available against the putative new leuco-cyte/endothelial markers in this latter group. Specific andwell-characterized reagents, whether monoclonal or poly-clonal, are needed not only for detecting these new “virtual”molecules but also for defining functional domains, for char-acterizing 3-D protein structure, and for analyzing protein-protein interactions. It may be added that cloning of genesequences often reveals multiple members of new or existingmolecular families (e.g., the Toll-like receptors) and mayidentify surface receptors that bind more than one ligand orvice versa, (e.g., the TALL-1 and APRIL ligands for TACIand BCMA). Furthermore, a number of leucocyte-associatedmarkers have been cloned from mice and other species, andalmost all will have human homologues. HLDA8 will providea forum for a range of antibody-based studies based on thisaccumulating corpus of genomic and proteomic data.

As in HLDA7 in which four new sections were added, itmay be possible to include neuronal cells in HLDA8. Manyneuronal cells express cell surface proteins found on leuco-cytes and vice versa (e.g., CD56, CD100, CD168, CD171).Furthermore, the guidance cues used by neuronal cells sharesimilarities to those involved in leucocyte extravasation, so theexpression of these molecules in common may reflect sharedbiological processes. It may also be noted that other moleculessuch as the mucins, thought to be primarily associated withepithelial cells, are now being described on leucocytes.

Table 3. Examples of possible future CD specificities (continued)

Molecule Mol. Size Cell types Comments References

M160 1453 aa Macrophages New member of scavenger [27]receptor cysteine-rich superfamily.

MARCO (Macrophage 520 aa Macrophages Class A scavenger receptor. [28, 29]receptor with collagenous Involved in bacterial clearance structure) in vivo.

TACI 293 aa B cells TNFR family member. [30]Receptor for TALL-1 and APRIL.

TREM-1 and TREM-2 Neutrophils and subset of Novel Ig superfamily receptors. [31, 32](Triggering receptors monocytes (TREM-1) and TREM-1 triggers neutrophil expressed on myeloid cells) macrophages (TREM-2). secretion (e.g. IL-8) and

degranulation. TREM-2 activates macrophages. Both associate with DAP12.

Abbreviations: NK = natural killer; TNFR = tumor necrosis factor receptor; VEGFR = vascular endothelial growth factor receptor; IL = interleukin.

Mason, André, Bensussan et al. 561

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8 Asanuma H, Takahashi S, Ishikawa M et al. A monoclonalantibody, 3G12, reacts with a novel surface molecule, Hal-1,with high expression in CD30-positive anaplastic large celllymphomas. Br J Haematol 1999;106:55-63.

9 Zocchi MR, Poggi A, Mariani S et al. Identification of a newsurface molecule expressed by human LGL and LAK cells pro-duction of a specific monoclonal antibody and comparison withother NK/LAK markers. Cell Immunol 1989;124:144-157.

10 Vitale M, Falco M, Castriconi R et al. Identification of NKp80,a novel triggering molecule expressed by human NK cells. EurJ Immunol 2001;31:233-242.

11 Roda-Navarro P, Arce I, Renedo M et al. Human KLRF1, anovel member of the killer cell lectin-like receptor gene fam-ily: molecular characterization, genomic structure, physicalmapping to the NK gene complex and expression analysis.Eur J Immunol 2000;30:568-576.

12 Bono P, Salmi M, Smith DJ et al. Cloning and characterizationof mouse vascular adhesion protein-1 reveals a novel moleculewith enzymatic activity. J Immunol 1998;160:5563-5571.

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14 Greiner A, Neumann M, Stingl S et al. Characterization ofWue-1, a novel monoclonal antibody that stimulates the growthof plasmacytoma cell lines. Virchows Arch 2000;437:372-379.

15 Madry C, Laabi Y, Callebaut I et al. The characterization ofmurine BCMA gene defines it as a new member of the tumornecrosis factor receptor superfamily. Int Immunol 1998;10:1693-1702.

16 Shu HB, Johnson H. B cell maturation protein is a receptor forthe tumor necrosis factor family member TALL-1. Proc NatlAcad Sci USA 2000;97:9156-9161.

17 Wang S, Zhu G, Chapoval AI et al. Costimulation of T cellsby B7-H2, a B7-like molecule that binds ICOS. Blood2000;96:2808-2813.

18 Colonna M, Samaridis J, Angman L. Molecular characteriza-tion of two novel C-type lectin-like receptors, one of which isselectively expressed in human dendritic cells. Eur JImmunol 2000;30:697-704.

19 Jackson DG, Hart DN, Starling G et al. Molecular cloning ofa novel member of the immunoglobulin gene superfamilyhomologous to the polymeric immunoglobulin receptor. EurJ Immunol 1992;22:1157-1163.

20 Green BJ, Clark GJ, Hart DN. The CMRF-35 mAb recog-nizes a second leukocyte membrane molecule with a domainsimilar to the poly Ig receptor. Int Immunol 1998;10:891-899.

21 Boles KS, Mathew PA. Molecular cloning of CS1, a novelhuman natural killer cell receptor belonging to the CD2 sub-set of the immunoglobulin superfamily. Immunogenetics2001;52:302-307.

22 Hartgers FC, Vissers JL, Looman MW et al. DC-STAMP, a novel multimembrane-spanning molecule preferentiallyexpressed by dendritic cells. Eur J Immunol 2000;30:3585-3590.

23 Stacey M, Lin HH, Hilyard KL et al. Human epidermal growthfactor (EGF) module-containing mucin-like hormone receptor 3is a new member of the EGF-TM7 family that recognizes a lig-and on human macrophages and activated neutrophils. J BiolChem 2001;276:18863-18870.

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26 Hatzivassiliou G, Miller I, Takizawa J et al. IRTA1 and IRTA2,novel immunoglobulin superfamily receptors expressed in Bcells and involved in chromosome 1q21 abnormalities in B cellmalignancy. Immunity 2001;14:277-289.

Finally, it remains to be established how HLDA8 andsubsequent Workshops should deal with lineage- or stage-restricted leucocyte molecules that are localized within thecell cytoplasm (or nucleus). Given the importance of manyof these molecules in signaling pathways initiated viaknown surface CD molecules, their identification and study

is an inevitable extension of the work of the first sevenHLDA Workshops. Whether a new “intracellular CD” cat-egorization scheme is devised for such molecules, they areof importance for many laboratories interested in humanhematopoietic cells, and their study will be among the aimsof the next Workshop.

562 CD Antigens 2001

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28 Elomaa O, Sankala M, Pikkarainen T et al. Structure of thehuman macrophage MARCO receptor and characterization ofits bacteria-binding region. J Biol Chem 1998;273:4530-4538.

29 Van der Laan LJ, Dopp EA, Haworth R et al. Regulation and func-tional involvement of macrophage scavenger receptor MARCO in clearance of bacteria in vivo. J Immunol 1999;162:939-947.

30 Xia XZ, Treanor J, Senaldi G et al. TACI is a TRAF-interactingreceptor for TALL-1, a tumor necrosis factor family memberinvolved in B cell regulation. J Exp Med 2000;192:137-143.

31 Bouchon A, Dietrich J, Colonna M. Cutting edge: inflamma-tory responses can be triggered by TREM-1, a novel receptorexpressed on neutrophils and monocytes. J Immunol2000;164:4991-4995.

32 Daws MR, Lanier LL, Seaman WE et al. Cloning and char-acterization of a novel mouse myeloid DAP12-associatedreceptor family. Eur J Immunol 2001;31:783-792.