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Clusters of Differentiation (CD)

cluster of differentiation

For medical students2 min readUpdated 2026-10-10

Clusters of differentiation (cluster of differentiation, commonly abbreviated as CD) are specific surface protein molecules expressed by cells of the immune system. Due to the unique profile of these antigens, cell types, stages of maturation, and functional states can be precisely identified, making them essential tools in modern immunology and diagnostics.

SpecificityEach cell lineage possesses a unique set (profile) of CD molecules distinguishing it from other leukocytes.

LocationPredominantly located on the plasma membrane (cell surface), though some molecules can localize intracellularly.

Chemical NatureProtein molecules predominantly belonging to the immunoglobulin and tumor necrosis factor receptor superfamilies.

QuantityThe WHO-classified list currently includes over 300 designated CD markers.

Biological Role and Expression Dynamics

CD antigens are not merely passive, static "tags." They are active participants in immunological processes performing numerous functions. Primarily, they act as receptors, ligands, and adhesion molecules, ensuring effective intercellular communication within the immune system.

The set of cluster of differentiation molecules on a cell surface is a dynamic indicator. Their expression directly depends on several factors:

The differentiation stage of the specific cell.
The degree of cellular maturity.
Membership in a particular subpopulation.

These markers are present on virtually all immune cells: T and B lymphocytes, macrophages, dendritic cells, and neutrophils. In clinical practice, monoclonal antibodies targeting CD antigens allow physicians and researchers to reliably differentiate cell populations and evaluate cellular maturation stages in detail.

World Health Organization Nomenclature

The classification of CD antigens, approved by the WHO, is based on the specificity of antibodies directed against human leukocyte antigens.

The nomenclature principle is straightforward: each newly discovered molecule is assigned a sequential number (e.g., CD1, CD2, and so on). Today, the list is extensive, encompassing over 300 established markers.

Originally created for white blood cells, this classification system has proven to be highly versatile. It now encompasses not only leukocytes but also specific surface antigens found on many other cell types throughout the body.

T and B Lymphocyte Markers

Each lymphocyte subpopulation possesses a strictly defined set of molecules determining its specific functions.

T Lymphocyte Markers:

CD3: The universal (pan-T) marker of all T lymphocytes. It is associated with the T-cell receptor (TCR) complex and is responsible for transducing the activating signal into the cell upon antigen binding.
CD4: The classic marker of T helper cells. It is a coreceptor whose primary function is the recognition of MHC class II molecules on the surface of antigen-presenting cells (APCs). Crucially, CD4 is also expressed on monocytes, macrophages, dendritic cells, and certain tumor cells.
CD8: The marker of cytotoxic T lymphocytes (CTLs). It also acts as a coreceptor, but unlike CD4, its function is to recognize MHC class I molecules on target cells.
CD28: A vital costimulatory molecule on T lymphocytes, essential for their full activation.

B Lymphocyte Markers: The primary specific markers of B cells are CD19, CD20, and CD21. Their main role involves direct participation in the complex processes of B-lymphocyte activation and subsequent proliferation.

NK Cell, Activation, Stem Cell, and Apoptosis Markers

In addition to standard T- and B-cell markers, specialized antigens govern specific functions or activation states:

CD16 (Natural Killer Cell Marker): A low-affinity receptor for immunoglobulin G (IgG) Fc regions (FcγRIII). Its presence enables NK cells to mediate antibody-dependent cellular cytotoxicity (ADCC).
CD25 (Activation Marker): Upregulated on the surface of both T and B lymphocytes upon activation (the alpha chain of the IL-2 receptor).
CD34: A key transmembrane phosphoglycoprotein marker used to identify hematopoietic stem cells (HSCs).
CD40: A costimulatory molecule required for productive interactions between antigen-presenting cells (APCs) and B lymphocytes.
CD95 (Fas/APO-1): A specific marker functioning as a death receptor (Death Receptor, DR). Its structural hallmark is an intracellular Death Domain (DD). Upon ligation, this domain triggers the apoptotic cascade—programmed cell death.

Mnemonic

B-cell markers are easy to remember because they form a consecutive sequence: CD19, CD20, and CD21.

Frequently asked questions

Which CD markers are specific to B lymphocytes?

Specific B-lymphocyte markers include molecules involved in activation, proliferation, and antigen recognition. Key B-cell antigens include:

CD19 — A strictly specific pan-B-cell marker.
CD20 — A specific marker involved in B-cell activation.
CD21 (CR2) — Complement receptor 2.
CD22 — A heavily expressed B-cell inhibitory coreceptor.
CD23 — A marker of follicular B2 cells.
CD79a and CD79b (Igα and Igβ) — Polypeptide chains forming the signaling component of the BCR complex.

B cells may also express CD32, CD43, CD45, CD62L, CD72, and CD81.

Which CD markers belong to the immunoglobulin superfamily?

The immunoglobulin superfamily includes various receptors, differentiation markers, and adhesion molecules. CD markers in this family include:

CD2, CD3, CD4, CD8 — T-cell coreceptors and differentiation markers.
CD28, CD152 (CTLA-4), ICOS, PD-1 — Costimulatory or regulatory molecules.
CD54 (ICAM-1) and CD106 (VCAM-1) — Adhesion molecules.
CD79a (Igα) and CD79b (Igβ) — Polypeptide chains of the B-cell receptor heterodimer.
CD90 (Thy-1) — An immunoglobulin superfamily member.
CD121 (IL-1R) — Cytokine receptor.

Which CD markers function as adhesion molecules?

Adhesion molecules include integrins, selectins, and immunoglobulin superfamily members that mediate migration and intercellular contact. Adhesion-related CD markers include:

CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1, CR3), CD11c/CD18 (p150/p95, CR4) — Leukocyte β2-integrins.
CD18 — Common leukocyte integrin β2 chain.
CD54 (ICAM-1) and CD106 (VCAM-1) — Immunoglobulin-like adhesion molecules.
CD62L (L-selectin) — Adhesion molecule on naïve T cells involved in homing.
CD15s — L-selectin ligand; defects in its expression impair leukocyte rolling.
CD34 — Endothelial molecule interacting with L-selectin during neutrophil capture.

What CD markers are expressed on the surface of natural killer (NK) cells?

Natural killer (NK) cells express the following surface markers:

CD16 — Low-affinity IgG receptor mediating antibody-dependent cellular cytotoxicity.
CD56 and CD94 — Characteristic NK-cell surface markers.
CD2 — Expressed on NK cells.
CD8 — Expressed on a subset of natural killer cells.
CD21 (CR2) — Complement receptor that can be expressed on NK cells.

Notably, NK cells lack T-cell receptor (TCR) markers.

What molecules are required for T-lymphocyte costimulation during activation?

T-cell activation requires interactions between costimulatory molecules on T cells and their respective ligands on antigen-presenting cells (APCs). Major costimulatory pairs include:

CD28 on the T cell interacts with CD80 (B7-1) and CD86 (B7-2) on the APC, providing essential costimulation and driving IL-2 secretion.
CD154 (CD40L) on the T cell binds to CD40 on the APC or B cell.
ICOS on the T helper cell interacts with ICOS-L on the APC.
OX40 on the T helper cell interacts with OX40L on the APC.

Adhesion molecules also facilitate T-B cell cooperation.

Which CD markers appear on lymphocytes upon activation?

During T-lymphocyte activation, specific membrane markers appear sequentially:

CD69 — The earliest activation antigen; appears on the surface within 2–3 hours.
CD25 — An early activation marker, the IL-2 receptor alpha chain; appears within 4 hours (also expressed on activated B cells).
CD71 — Transferrin receptor; expressed around 24 hours, crucial for cellular proliferation.
MHC-II — Late activation markers on human T cells; expressed on days 3–6.
CD95 — Upregulated on activated T cells; functions as a Fas/APO death receptor triggering apoptosis.

Adhesion molecules, including VLA group β1-integrins, also appear during late activation stages.

Can the T-helper marker (CD4) be found on non-lymphoid cells?

Yes, aside from T-helper cells, the CD4 molecule is also expressed on the surface of monocytes, macrophages, dendritic cells, and occasionally on certain tumor cells.

What is the function of the CD3 molecule?

CD3 is a pan-T marker present on all T lymphocytes. As part of the T-cell receptor (TCR) complex, this molecule transmits activating signals into the cell interior upon successful antigen binding.

What happens when the CD95 receptor interacts with its ligand?

CD95 (Fas) functionally acts as a "death receptor." Binding to the Fas ligand triggers its intracellular "death domain" (DD), initiating the apoptotic cascade.

Go deeper

Detailed structure of the T-cell receptor (TCR) complex and the role of CD3 in signal transduction
Mechanism of MHC class I and class II recognition involving CD8 and CD4 coreceptors
The pathway of antibody-dependent cellular cytotoxicity (ADCC) mediated by CD16
CD40 and CD40L interactions between antigen-presenting cells and B lymphocytes
Intracellular apoptotic signaling cascades triggered by the CD95 death domain (DD)