View source for Cluster of differentiation

{{Short description|Classification in immunology}}
{{See also|List of human clusters of differentiation}}
The '''cluster of differentiation''' (also known as '''cluster of designation''' or '''classification determinant''' and often abbreviated as '''CD''') is a protocol used for the identification and investigation of [[cell surface molecule]]s providing targets for [[immunophenotyping]] of cells.<ref>{{Cite journal |last1=CHAN, J. K. C. |last2=NG, C. S. |last3=HUI, P. K. |year=1988 |title=A simple guide to the terminology and application of leucocyte monoclonal antibodies |journal=Histopathology |volume=12 |issue=5 |pages=461–480 |doi=10.1111/j.1365-2559.1988.tb01967.x |pmid=3294157 |s2cid=6823812}}</ref> In terms of physiology, CD molecules can act in numerous ways, often acting as [[receptor (biochemistry)|receptors]] or [[ligand (biochemistry)|ligands]] important to the cell. A [[Biochemical cascade|signal cascade]] is usually initiated, altering the behavior of the cell (see [[cell signaling]]). Some CD proteins do not play a role in cell signaling, but have other functions, such as [[cell adhesion]]. <!--There are approximately 250 different proteins.-->[[List of human clusters of differentiation|CD for humans]] is numbered up to 371 ({{As of|2016|04|21|lc=y}}).<ref name="hcdm">{{Cite web |title=HCDM, responsible for HLDA workshop and CD molecules |url=http://www.hcdm.org/MoleculeInformation/tabid/54/Default.aspx |url-status=dead |archive-url=https://web.archive.org/web/20160420020358/http://www.hcdm.org/MoleculeInformation/tabid/54/Default.aspx |archive-date=2016-04-20 |access-date=2016-04-21 |publisher=Human Cell Differentiation Molecules Council (successor to the HLDA Workshops)}}</ref><ref name="pmid16020511">{{Cite journal |vauthors=Zola H, Swart B, Banham A, Barry S, Beare A, Bensussan A, Boumsell L, D Buckley C, Bühring HJ, Clark G, Engel P, Fox D, Jin BQ, Macardle PJ, Malavasi F, Mason D, Stockinger H, Yang X |year=2007 |title=CD molecules 2006--human cell differentiation molecules. |journal=J Immunol Methods |volume=319 |issue=1–2 |pages=1–5 |doi=10.1016/j.jim.2006.11.001 |pmid=17174972}}</ref>

== Nomenclature ==
The '''CD nomenclature''' was proposed and established in the 1st International Workshop and Conference on Human [[Leukocyte]] Differentiation [[Antigen]]s (HLDA), held in [[Paris, France|Paris]] in 1982.<ref name="pmid6239187">{{Cite journal |vauthors=Bernard A, Boumsell L |year=1984 |title=[Human leukocyte differentiation antigens] |journal=Presse Med |language=fr |volume=13 |issue=38 |pages=2311–6 |pmid=6239187}}</ref><ref name="pmid6240938">{{Cite journal |vauthors=Fiebig H, Behn I, Gruhn R, Typlt H, Kupper H, Ambrosius H |year=1984 |title=Charakterisierung einer Serie von monoklonalen Antikörpern gegen humane T-Zellen |trans-title=Characterization of a series of monoclonal antibodies against human T cells |journal=Allerg Immunol (Leipz) |language=de |volume=30 |issue=4 |pages=242–50 |pmid=6240938}}</ref> This system was intended for the classification of the many [[monoclonal antibodies]] (mAbs) generated by different laboratories around the world against [[epitope]]s on the surface molecules of [[white blood cell|leukocyte]]s (white blood cells). Since then, its use has expanded to many other cell types, and more than 370 CD unique clusters and subclusters have been identified. The proposed surface molecule is assigned a CD number once two specific monoclonal antibodies are shown to bind to the molecule. If the molecule has not been well characterized or has only one mAb, it is usually given the provisional indicator "w" (as in "[[CD186|CDw186]]").<ref>{{Cite journal |last1=Zola |first1=Heddy |last2=Swart |first2=Bernadette |last3=Banham |first3=Alison |last4=Barry |first4=Simon |last5=Beare |first5=Alice |last6=Bensussan |first6=Armand |last7=Boumsell |first7=Laurence |last8=D. Buckley |first8=Chris |last9=Bühring |first9=Hans-Jörg |last10=Clark |first10=Georgina |last11=Engel |first11=Pablo |last12=Fox |first12=David |last13=Jin |first13=Bo-Quan |last14=Macardle |first14=Peter J. |last15=Malavasi |first15=Fabio |date=January 2007 |title=CD molecules 2006 — Human cell differentiation molecules |journal=Journal of Immunological Methods |volume=319 |issue=1–2 |pages=1–5 |doi=10.1016/j.jim.2006.11.001 |quote=Clarify and bring up to date earlier provisional (CDw) designations. |last16=Mason |first16=David |last17=Stockinger |first17=Hannes |last18=Yang |first18=Xifeng |pmid=17174972 }}</ref>

For instance, [[CD2]] mAbs are reagents that react with a 50‐kDa [[transmembrane]] [[glycoprotein]] expressed on [[T cell]]s. The CD designations were used to describe the recognized molecules but had to be clarified by attaching the term antigen or molecule to the designation (e.g., CD2 molecule). Currently, "CD2" is generally used to designate the molecule, and "CD2 [[antibody]]" is used to designate the antibody.<ref name="Monoclonal Antibodies to Human Cell">{{Cite journal |last1=Beare |first1=Alice |last2=Stockinger |first2=Hannes |last3=Zola |first3=Heddy |last4=Nicholson |first4=Ian |year=2008 |title=Monoclonal Antibodies to Human Cell Surface Antigens |journal=Current Protocols in Immunology |volume=80 |issue=1 |pages=A.4A.1–A.4A.73 |doi=10.1002/0471142735.ima04as80 |pmc=7162157 |pmid=18432634}}</ref>

Cell populations are usually defined using a '+' or a '−' symbol to indicate whether a certain cell fraction expresses or lacks a CD molecule. For example, a "[[CD34]]+, [[CD31]]−" cell is one that expresses CD34 but not CD31. This CD combination typically corresponds to a [[stem cell]], as opposed to a fully differentiated [[endothelial cell]]. Some cell populations can also be defined as <sup>hi</sup>, <sup>mid</sup>, or <sup>low</sup> (alternatively, <sup>bright</sup>, <sup>mid</sup>, or <sup>dim</sup>), indicating an overall [[Expressivity (genetics)|variability]] in CD [[genetic expression|expression]], particularly when compared to other cells being studied. A review of the development of T cells in the [[thymus]] uses this nomenclature to identify cells transitioning from CD4<sup>mid</sup>/CD8<sup>mid</sup> double-positive cells to CD4<sup>hi</sup>/CD8<sup>mid</sup>.<ref name="pmid19151747">{{Cite journal |vauthors=Ho IC, Tai TS, Pai SY |date=February 2009 |title=GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation |journal=Nature Reviews Immunology |volume=9 |issue=2 |pages=125–35 |doi=10.1038/nri2476 |pmc=2998182 |pmid=19151747}}</ref>

==Human Leukocyte Differentiation Antigen Workshops==
Since 1982 there have been nine Human Leukocyte Differentiation Antigen Workshops culminating in a conference.
{| class="wikitable"
! Workshop !! City !! Year !! CDs assigned !! Reference
|-
| I || [[Paris]] || 1982 || 1-15 || <ref>{{Cite book |last=Bernard |first=AR |title=Leucocyte Typing: Human Leucocyte Differentiation Antigens Detected by Monoclonal antibodies |date=1984 |publisher=Berlin: Springer-Verlag |display-authors=etal}}</ref>
|-
| II || [[Boston]] || 1984 || 16-26 || <ref>{{Cite book |last=Reinherz |first=EL |title=Leukocyte Typing II |date=1985 |publisher=New York: Springer-Verlag |display-authors=etal}}</ref>
|-
| III || [[Oxford]] || 1986 || 27-45 || <ref>{{Cite book |last=McMichael |first=AJ |title=Leucocyte Typing III. White Cell Differentiation Antigens. |date=1987 |publisher=Oxford University Press |display-authors=etal}}</ref>
|-
| IV || [[Vienna]] || 1989 || 46-78 || <ref>{{Cite book |last=Knapp |first=W |title=Leucocyte Typing IV |date=1989 |publisher=Oxford University Press |display-authors=etal}}</ref>
|-
| V || [[Boston]] || 1993 || 79-130 || <ref>{{Cite book |last=Schlossman |first=SF |title=Leucocyte Typing V: White cell differentiation antigens |date=1995 |publisher=Oxford University Press |display-authors=etal}}</ref>
|-
| VI || [[Kobe]] || 1996 || 131-166 || <ref>{{Cite book |last=Kishimoto |first=T |title=Leucocyte Typing VI |date=1997 |publisher=Garland Publishing |display-authors=etal}}</ref>
|-
| VII || [[Harrogate]] || 2000 || 167-247 || <ref>{{Cite book |last=Mason |first=D. |title=Leucocyte Typing VII |date=2002 |publisher=Oxford University Press |display-authors=etal}}</ref>
|-
| VIII || [[Adelaide]] || 2004 || 248-339 || <ref>{{Cite journal |vauthors=Zola H, Swart B, Nicholson I, Aasted B, Bensussan A, Boumsell L, Buckley C, Clark G, Drbal K, Engel P, Hart D, Horejsí V, Isacke C, Macardle P, Malavasi F, Mason D, Olive D, Saalmueller A, Schlossman SF, Schwartz-Albiez R, Simmons P, Tedder TF, Uguccioni M, Warren H |date=November 1, 2005 |title=CD molecules 2005: human cell differentiation molecules |journal=Blood |volume=106 |issue=9 |pages=3123–6 |doi=10.1182/blood-2005-03-1338 |pmid=16020511 |doi-access=free}}</ref>
|-
| IX || [[Barcelona]] || 2010 || 340-364 || <ref>{{Cite journal |date=30 January 2011 |title=Proceedings of the 9th International Workshop on Human Leukocyte Differentiation Antigens. March 2010. Barcelona, Spain. |journal=Immunol. Lett. |volume=134 |issue=2 |pages=103–187}}</ref>
|-
| X || [[Wollongong]] || 2014 || 365-371 ||
|}

==Immunophenotyping==
[[File:Cluster of differentiation.svg|thumb|Cluster of Differentiation]]
The CD system is commonly used as cell markers in [[immunophenotyping]], allowing cells to be defined based on what molecules are present on their surface. These markers are often used to associate cells with certain [[immune system|immune function]]s. While using one CD molecule to define populations is uncommon (though a few examples exist), combining markers has allowed for cell types with very specific definitions within the immune system.{{citation needed|date=May 2020}}

CD molecules are utilized in [[cell sorting]] using various methods, including [[flow cytometry]].{{cn|date=December 2024}}

{| class="wikitable"
! Type of cell !! CD markers
 |-
 | [[stem cell]]s || [[CD34]]+, [[CD31]]-, [[CD117]]
 |-
 | all [[leukocyte]] groups || [[CD45]]+
 |-
 | [[Granulocyte]]  || CD45+, [[CD11b]], [[CD15]]+, [[CD24]]+, [[CD114]]+, CD182+<ref name="docs.abcam.com">{{Cite web |year=2009 |title=CD Antigens |url=http://docs.abcam.com/pdf/immunology/cdantigen_poster.pdf |access-date=2014-11-22 |publisher=abcam}}</ref>
 |-
 | [[Monocyte]] || CD4, CD45+, [[CD14]]+, [[CD114]]+,  [[CD11a]], CD11b, CD91+,<ref name="docs.abcam.com" /> [[CD16]]+<ref>{{Cite journal |vauthors=Passlick B, Flieger D, Ziegler-Heitbrock HW |year=1989 |title=Identification and characterization of a novel monocyte subpopulation in human peripheral blood |journal=[[Blood (journal)|Blood]] |volume=74 |issue=7 |pages=2527–2534 |doi=10.1182/blood.V74.7.2527.2527 |pmid=2478233 |doi-access=free}}</ref>
 |-
 | [[T lymphocyte]] || CD45+, [[CD3 (immunology)|CD3]]+
 |-
 | [[T helper cell]] || CD45+, CD3+, [[CD4]]+
 |-
 | [[T regulatory cell]] ||[[CD4]], [[CD25]], [[FOXP3|FOXP3 (a transcription factor)]]
 |-
 | [[Cytotoxic T cell]] || CD45+, CD3+, [[CD8]]+
 |-
 | [[B lymphocyte]] || CD45+, [[CD19]]+, [[CD20]]+, [[CD24]]+, [[CD38]], [[CD22]]
 |-
 | [[Thrombocyte]] || CD45+, [[CD61]]+
 |-
 | [[Natural killer cell]] || [[CD16]]+, [[CD56]]+, CD3-, [[CD31]], [[CD30]], CD38
|}

Two commonly used CD molecules are [[CD4]] and [[CD8]], which are, in general, used as markers for [[T helper cell|helper]] and [[cytotoxic T cell|cytotoxic]] T cells, respectively. These molecules are defined in combination with CD3+, as some other leukocytes also express these CD molecules (some macrophages express low levels of CD4; [[dendritic cells]] express high levels of CD8). [[Human immunodeficiency virus]] binds CD4 and a [[chemokine]] receptor on the surface of a T helper cell to gain entry. The number of CD4 and CD8 T cells in blood is often used to monitor the progression of [[HIV infection]].{{cn|date=December 2024}}

==Physiological functions==
While CD molecules are very useful in defining leukocytes, they are not merely markers on the [[cell surface]]. Though only a fraction of known CD molecules have been thoroughly characterised, most of them have important functions. In the example of CD4 and CD8, these molecules are critical in [[antigen]] recognition. Others (e.g., [[CD135]]) act as cell surface receptors for [[growth factor]]s. Recently, the marker CD47 was found to have anti-[[phagocyte|phagocytic]] signals to macrophages and inhibit [[natural killer]] (NK) cells. This enabled researchers to apply CD47 as a potential target to attenuate [[immune rejection]].<ref>{{Cite web |date=18 February 2019 |title=CRISPR Gene Editing Makes Stem Cells 'Invisible' to Immune System &#124; UC San Francisco |url=https://www.ucsf.edu/news/2019/02/413311/crispr-gene-editing-makes-stem-cells-invisible-immune-system}}</ref><ref>{{Cite journal |last1=Deuse |first1=T |last2=Hu |first2=X |date=2019 |title=Hypoimmunogenic derivatives of induced pluripotent stem cells evade immune rejection in fully immunocompetent allogeneic recipients. |journal=Nature Biotechnology |volume=37 |issue=3 |pages=252–258 |doi=10.1038/s41587-019-0016-3 |pmc=6419516 |pmid=30778232}}</ref>

==See also==
* [[Antibodies]]
* [[Transferrin receptor 1|CD71/Transferrin receptor-1]]
* [[CD13]] marker for kidney disorder
* [[CD33]] marker for [[Acute myeloid leukemia|AML]] treatment
* [[CD4+/CD8+ ratio]]
* [[Immune system]]
* [[Immune tolerance]]
* [[Leukocytes]]
* [[Major histocompatibility complex]]
* [[Signal transduction]]

==References==
{{Reflist|2}}

==External links==
* [https://web.archive.org/web/20160420020358/http://www.hcdm.org/MoleculeInformation/tabid/54/Default.aspx Molecule search] maintained by the Human Cell Differentiation Molecules Council (successor to the HLDA Workshops)
<!-- This should probably remain at the top of the list -->
* [http://www.immunologylink.com/cdantigen.html Table of CD Antigens]
* [http://www.sciencegateway.org/resources/prow/index.html CD list] {{Webarchive|url=https://web.archive.org/web/20161207034249/http://www.sciencegateway.org/resources/prow/index.html |date=2016-12-07 }} Protein Reviews On The Web
* Yet another [http://pathologyoutlines.com/cdmarkers.html list of CD molecules], at PathologyOutlines.com
* [http://www.ebioscience.com/ebioscience/litreq.asp Wall charts] of CD molecules and other cytokines, with colors, arrows from one cell to another, from eBioscience.
* [http://umr976.simdif.com// Skin Research Center lab] {{Webarchive|url=https://web.archive.org/web/20181114011309/http://umr976.simdif.com// |date=2018-11-14 }} Hopital St Louis, Paris (France) Dir. Dr. A. Bensussan

{{Clusters of differentiation}}
{{Surface antigens}}
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[[Category:Anatomical pathology]]
[[Category:Clusters of differentiation|*]]
[[Category:Antigens]]