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CD4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1CDH, 1CDI, 1CDJ, 1CDU, 1CDY, 1G9M, 1G9N, 1GC1, 1JL4, 1Q68, 1RZJ, 1RZK, 1WIO, 1WIP, 1WIQ, 2B4C, 2JKR, 2JKT, 2KLU, 2NXY, 2NXZ, 2NY0, 2NY1, 2NY2, 2NY3, 2NY4, 2NY5, 2NY6, 2QAD, 3B71, 3CD4, 3JWD, 3JWO, 3LQA, 3O2D, 3S5L, 3T0E, 4JM2, 1WBR, 3S4S, 4H8W, 4P9H, 4Q6I, 4R2G, 4R4H, 4RQS, 3J70, 5A7X, 5A8H, 5CAY
Identifiers
Aliases	CD4, CD4mut, CD4 molecule, OKT4D, IMD79
External IDs	OMIM: 186940; MGI: 88335; HomoloGene: 513; GeneCards: CD4; OMA:CD4 - orthologs
Gene location (Human) Chr. Chromosome 12 (human) Band 12p13.31 Start 6,786,858 bp End 6,820,799 bp
Gene location (Mouse) Chr. Chromosome 6 (mouse) Band 6 F2|6 59.17 cM Start 124,841,655 bp End 124,865,184 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in granulocyte monocyte lymph node spleen appendix gallbladder thymus upper lobe of left lung right lung right lobe of liver Top expressed in thymus lymph node mesenteric lymph nodes blood spleen zygote external carotid artery internal carotid artery superior frontal gyrus molar More reference expression data BioGPS n/a
Gene ontology Molecular function transmembrane signaling receptor activity virus receptor activity protein homodimerization activity zinc ion binding extracellular matrix structural constituent enzyme binding immunoglobulin binding protein binding coreceptor activity interleukin-16 binding interleukin-16 receptor activity MHC class II protein binding identical protein binding protein tyrosine kinase binding signaling receptor activity protein kinase binding signaling receptor binding Cellular component endoplasmic reticulum lumen integral component of membrane early endosome membrane cell surface endoplasmic reticulum membrane membrane raft T cell receptor complex external side of plasma membrane plasma membrane clathrin-coated vesicle membrane integral component of plasma membrane Biological process transmembrane receptor protein tyrosine kinase signaling pathway defense response to Gram-negative bacterium positive regulation of protein kinase activity mitigation of host defenses by virus positive regulation of calcium-mediated signaling signal transduction helper T cell enhancement of adaptive immune response T cell selection response to estradiol induction by virus of host cell-cell fusion adaptive immune response response to vitamin D T cell differentiation cell surface receptor signaling pathway positive regulation of T cell proliferation positive regulation of peptidyl-tyrosine phosphorylation enzyme linked receptor protein signaling pathway T cell activation positive regulation of T cell activation maintenance of protein location in cell cytokine production T cell receptor signaling pathway immune system process positive regulation of calcium ion transport into cytosol regulation of T cell activation immune response cell adhesion viral process fusion of virus membrane with host plasma membrane membrane organization positive regulation of protein phosphorylation positive regulation of kinase activity interleukin-15-mediated signaling pathway positive regulation of I-kappaB kinase/NF-kappaB signaling positive regulation of MAPK cascade positive regulation of monocyte differentiation positive regulation of transcription, DNA-templated positive regulation of viral entry into host cell regulation of calcium ion transport positive regulation of ERK1 and ERK2 cascade cellular response to granulocyte macrophage colony-stimulating factor stimulus cytokine-mediated signaling pathway macrophage differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 920 12504 Ensembl ENSG00000010610 ENSMUSG00000023274 UniProt P01730 P06332 RefSeq (mRNA) NM_000616 NM_001195014 NM_001195015 NM_001195016 NM_001195017 NM_001382705 NM_001382706 NM_001382707 NM_001382714 NM_013488 RefSeq (protein) NP_000607 NP_001181943 NP_001181944 NP_001181945 NP_001181946 NP_001369634 NP_001369635 NP_001369636 NP_001369643 NP_038516 Location (UCSC) Chr 12: 6.79 – 6.82 Mb Chr 6: 124.84 – 124.87 Mb PubMed search
Wikidata
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CD4, Cluster of differentiation 4, extracellular
structure of T cell surface glycoprotein cd4, monoclinic crystal form
Identifiers
Symbol	CD4-extrcel
Pfam	PF09191
InterPro	IPR015274
SCOP2	1cid / SCOPe / SUPFAM
OPM superfamily	193
OPM protein	2klu
CDD	cd07695
Membranome	27
Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 (after the OKT4 monoclonal antibody that reacted with it) before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene.

CD4+ T helper cells are white blood cells that are an essential part of the human immune system. They are often referred to as CD4 cells, T helper cells or T4 cells. They are called helper cells because one of their main roles is to send signals to other types of immune cells, including CD8 killer cells, which then destroy the infectious particle. If CD4 cells become depleted, for example in untreated HIV infection, or following immune suppression prior to a transplant, the body is left vulnerable to a wide range of infections that it would otherwise have been able to fight.

Structure

Like many cell surface receptors/markers, CD4 is a member of the immunoglobulin superfamily.

It has four immunoglobulin domains (D₁ to D₄) that are exposed on the extracellular surface of the cell:

• D₁ and D₃ resemble immunoglobulin variable (IgV) domains.
• D₂ and D₄ resemble immunoglobulin constant (IgC) domains.

The immunoglobulin variable (IgV) domain of D₁ adopts an immunoglobulin-like β-sandwich fold with seven β-strands in two β-sheets, in a Greek key topology.

CD4 interacts with the β₂-domain of MHC class II molecules through its D₁ domain. T cells displaying CD4 molecules (and not CD8) on their surface, therefore, are specific for antigens presented by MHC II and not by MHC class I (they are MHC class II-restricted). MHC class I contains Beta-2 microglobulin.

The short cytoplasmic/intracellular tail (C) of CD4 contains a special sequence of amino acids that allow it to recruit and interact with the tyrosine kinase Lck.

Function

CD4 is a co-receptor of the T cell receptor (TCR) and assists the latter in communicating with antigen-presenting cells. The TCR complex and CD4 bind to distinct regions of the antigen-presenting MHC class II molecule. The extracellular D₁ domain of CD4 binds to the β2 region of MHC class II. The resulting close proximity between the TCR complex and CD4 allows the tyrosine kinase Lck bound to the cytoplasmic tail of CD4 to phosphorylate tyrosine residues of immunoreceptor tyrosine activation motifs (ITAMs) on the cytoplasmic domains of CD3 to amplify the signal generated by the TCR. Phosphorylated ITAMs on CD3 recruit and activate SH2 domain-containing protein tyrosine kinases (PTK), such as ZAP70, to further mediate downstream signalling through tyrosine phosphorylation. These signals lead to the activation of transcription factors, including NF-κB, NFAT, AP-1, to promote T cell activation.

CD4 is closely related to LAG-3, and together they form an evolutionary conserved system from the level of sharks competing for binding Lck by conserved motifs in their cytoplasmic tails: CD4 through a Cys-X-Cys/His motif and LAG-3 through an immunoreceptor tyrosine-based inhibition motif like (ITIM-like) motif. LAG-3, which is an inhibitory receptor, is upregulated in activated T cells as a kind of negative feedback loop.

Other interactions

CD4 has also been shown to interact with SPG21, and Uncoordinated-119 (Unc-119).

Disease

HIV infection

HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its viral envelope protein known as gp120. The binding to CD4 creates a shift in the conformation of gp120 allowing HIV-1 to bind to a co-receptor expressed on the host cell. These co-receptors are chemokine receptors CCR5 or CXCR4. Following a structural change in another viral protein (gp41), HIV inserts a fusion peptide into the host cell that allows the outer membrane of the virus to fuse with the cell membrane.

HIV pathology

HIV infection leads to a progressive reduction in the number of T cells expressing CD4. Medical professionals refer to the CD4 count to decide when to begin treatment during HIV infection, although recent medical guidelines have changed to recommend treatment at all CD4 counts as soon as HIV is diagnosed. A CD4 count measures the number of T cells expressing CD4. While CD4 counts are not a direct HIV test—e.g. they do not check the presence of viral DNA, or specific antibodies against HIV—they are used to assess the immune system of a patient.

National Institutes of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count Normal blood values are usually expressed as the number of cells per microliter (μL, or equivalently, cubic millimeter, mm) of blood, with normal values for CD4 cells being 500–1200 cells/mm. Patients often undergo treatments when the CD4 counts reach a level of 350 cells per microliter in Europe but usually around 500/μL in the US; people with less than 200 cells per microliter are at high risk of contracting AIDS defined illnesses. Medical professionals also refer to CD4 tests to determine efficacy of treatment.

Viral load testing provides more information about the efficacy for therapy than CD4 counts. For the first 2 years of HIV therapy, CD4 counts may be done every 3–6 months. If a patient's viral load becomes undetectable after 2 years then CD4 counts might not be needed if they are consistently above 500/mm. If the count remains at 300–500/mm, then the tests can be done annually. It is not necessary to schedule CD4 counts with viral load tests and the two should be done independently when each is indicated.

Other diseases

CD4 continues to be expressed in most neoplasms derived from T helper cells. It is therefore possible to use CD4 immunohistochemistry on tissue biopsy samples to identify most forms of peripheral T cell lymphoma and related malignant conditions. The antigen has also been associated with a number of autoimmune diseases such as vitiligo and type I diabetes mellitus.

T-cells play a large part in autoinflammatory diseases. When testing a drug's efficacy or studying diseases, it is helpful to quantify the amount of T-cells on fresh-frozen tissue with CD4+, CD8+, and CD3+ T-cell markers (which stain different markers on a T-cell – giving different results).

See also

• CD4+ T cells and antitumor immunity

References

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Further reading

• Miceli MC, Parnes JR (1993). "Role of CD4 and CD8 in T cell activation and differentiation". Advances in Immunology Volume 53. Vol. 53. pp. 59–122. doi:10.1016/S0065-2776(08)60498-8. ISBN 978-0-12-022453-1. PMID 8512039.
• Geyer M, Fackler OT, Peterlin BM (July 2001). "Structure--function relationships in HIV-1 Nef". EMBO Reports. 2 (7): 580–585. doi:10.1093/embo-reports/kve141. PMC 1083955. PMID 11463741.
• Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M (April 2003). "HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication". Journal of Biosciences. 28 (3): 323–335. doi:10.1007/BF02970151. PMID 12734410. S2CID 33749514.
• Bénichou S, Benmerah A (January 2003). "[The HIV nef and the Kaposi-sarcoma-associated virus K3/K5 proteins: "parasites"of the endocytosis pathway]". Médecine/Sciences. 19 (1): 100–106. doi:10.1051/medsci/2003191100. PMID 12836198.
• Leavitt SA, SchOn A, Klein JC, Manjappara U, Chaiken IM, Freire E (February 2004). "Interactions of HIV-1 proteins gp120 and Nef with cellular partners define a novel allosteric paradigm". Current Protein & Peptide Science. 5 (1): 1–8. doi:10.2174/1389203043486955. PMID 14965316.
• Tolstrup M, Ostergaard L, Laursen AL, Pedersen SF, Duch M (April 2004). "HIV/SIV escape from immune surveillance: focus on Nef". Current HIV Research. 2 (2): 141–151. doi:10.2174/1570162043484924. PMID 15078178.
• Hout DR, Mulcahy ER, Pacyniak E, Gomez LM, Gomez ML, Stephens EB (July 2004). "Vpu: a multifunctional protein that enhances the pathogenesis of human immunodeficiency virus type 1". Current HIV Research. 2 (3): 255–270. doi:10.2174/1570162043351246. PMID 15279589.
• Joseph AM, Kumar M, Mitra D (January 2005). "Nef: "necessary and enforcing factor" in HIV infection". Current HIV Research. 3 (1): 87–94. doi:10.2174/1570162052773013. PMID 15638726.
• Anderson JL, Hope TJ (April 2004). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS Reports. 1 (1): 47–53. doi:10.1007/s11904-004-0007-x. PMID 16091223. S2CID 34731265.
• Li L, Li HS, Pauza CD, Bukrinsky M, Zhao RY (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions". Cell Research. 15 (11–12): 923–934. doi:10.1038/sj.cr.7290370. PMID 16354571.
• Stove V, Verhasselt B (January 2006). "Modelling thymic HIV-1 Nef effects". Current HIV Research. 4 (1): 57–64. doi:10.2174/157016206775197583. PMID 16454711.

External links

• CD1+Antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Mouse CD Antigen Chart
• Human CD Antigen Chart
• Human Immunodeficiency Virus Glycoprotein 120
• Human CD4 genome location and CD4 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P01730 (T-cell surface glycoprotein CD4) at the PDBe-KB.

• Genes on human chromosome 12
• Clusters of differentiation
• Glycoproteins
• Immunology
• Protein domains
• T cells