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15  structures 57  species 3  interactions 74  sequences 14  architectures

Family: CD4-extracel (PF09191)

Summary: CD4, extracellular

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This is the Wikipedia entry entitled "CD4". More...

CD4 Edit Wikipedia article

Available structures
PDB Ortholog search: PDBe RCSB
Aliases CD4, CD4mut, CD4 molecule
External IDs MGI: 88335 HomoloGene: 513 GeneCards: CD4
Species Human Mouse
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC) Chr 12: 6.79 – 6.82 Mb Chr 6: 124.86 – 124.89 Mb
PubMed search [1] [2]
View/Edit Human View/Edit Mouse
CD4, Cluster of differentiation 4, extracellular
PDB 1wip EBI.jpg
structure of t-cell surface glycoprotein cd4, monoclinic crystal form
Symbol CD4-extrcel
Pfam PF09191
InterPro IPR015274
SCOP 1cid
OPM superfamily 230
OPM protein 2klu
CDD cd07695
Image of CD4 co-receptor binding to MHC (Major Histocompatibility Complex) non-polymorphic region.

In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein found on the surface of immune cells such as T helper 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.[3] In humans, the CD4 protein is encoded by the CD4 gene.[4][5]

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.


Schematic representation of CD4 receptor.

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.

CD4 uses its D1 domain to interact with the β2-domain of MHC class II molecules. T cells expressing 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 interact with the lck molecule.


CD4 is a co-receptor that assists the T cell receptor (TCR) in communicating with an antigen-presenting cell. Using its intracellular domain, CD4 amplifies the signal generated by the TCR by recruiting an enzyme, the tyrosine kinase Lck, which is essential for activating many molecular components of the signaling cascade of an activated T cell. Various types of T helper cells are thereby produced. CD4 also interacts directly with MHC class II molecules on the surface of the antigen-presenting cell using its extracellular domain. The extracellular domain adopts an immunoglobulin-like beta-sandwich with seven strands in 2 beta sheets, in a Greek key topology.[6]

During antigen presentation, both the TCR complex and CD4 are recruited to bind to different regions of the MHCII molecule (α1/β1 and β2, respectively) . Close proximity between the TCR complex and CD4 in this situation means the Lck kinase bound to the cytoplasmic tail of CD4 is able to tyrosine-phosphorylate the Immunoreceptor tyrosine activation motifs (ITAM) present on the cytoplasmic domains of CD3. Phosphorylated ITAM motifs on CD3 recruits and activates SH2 domain-containing protein tyrosine kinases (PTK) such as Zap70 to further mediate downstream signal transduction via tyrosine phosphorylation, leading to transcription factor activation including NF-κB and consequent T cell activation.[citation needed]

Other interactions

CD4 has also been shown to interact with SPG21,[7] Lck[8][9][10][11][12] and Protein unc-119 homolog.[13]


HIV infection

HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its viral envelope protein known as gp120.[14] 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.[citation needed]

National Institutes of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count[15] Normal blood values are usually expressed as the number of cells per microliter (μL, or equivalently, cubic millimeter, mm3) of blood, with normal values for CD4 cells being 500–1200 cells/mm3.[16] 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.[citation needed]

Viral load testing provides more information about the efficacy for therapy than CD4 counts.[17] For the first 2 years of HIV therapy, CD4 counts may be done every 3–6 months.[17] If a patient's viral load becomes undetectable after 2 years then CD4 counts might not be needed if they are consistently above 500/mm3.[17] If the count remains at 300–500/mm3, then the tests can be done annually.[17] It is not necessary to schedule CD4 counts with viral load tests and the two should be done independently when each is indicated.[17]

Reference ranges for blood tests of white blood cells, comparing CD4+ cell amount (shown in green-yellow) with other cells.

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.[18] The antigen has also been associated with a number of autoimmune diseases such as vitiligo and type I diabetes mellitus.[19]

T-cells play a large part in autoinflammatory diseases.[20] 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).[21]

See also


  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ Bernard A, Boumsell L, Hill C (1984). "Joint Report of the First International Workshop on Human Leucocyte Differentiation Antigens by the Investigators of the Participating Laboratories". In Bernard A, Boumsell L, Dausset J, Milstein C, Schlossman SF. Leucocyte typing: human leucocyte differentiation antigens detected by monoclonal antibodies: specification, classification, nomenclature. Berlin: Springer. pp. 45–48. ISBN 0-387-12056-4. doi:10.1007/978-3-642-68857-7_3. Report on the first international references workshop sponsored by INSERM, WHO and IUIS 
  4. ^ Isobe M, Huebner K, Maddon PJ, Littman DR, Axel R, Croce CM (June 1986). "The gene encoding the T-cell surface protein T4 is located on human chromosome 12". Proc. Natl. Acad. Sci. U.S.A. 83 (12): 4399–402. Bibcode:1986PNAS...83.4399I. PMC 323740Freely accessible. PMID 3086883. doi:10.1073/pnas.83.12.4399. 
  5. ^ Ansari-Lari MA, Muzny DM, Lu J, Lu F, Lilley CE, Spanos S, Malley T, Gibbs RA (April 1996). "A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13". Genome Res. 6 (4): 314–26. PMID 8723724. doi:10.1101/gr.6.4.314. 
  6. ^ Brady RL, Dodson EJ, Dodson GG, Lange G, Davis SJ, Williams AF, Barclay AN (May 1993). "Crystal structure of domains 3 and 4 of rat CD4: relation to the NH2-terminal domains". Science. 260 (5110): 979–83. Bibcode:1993Sci...260..979B. PMID 8493535. doi:10.1126/science.8493535. 
  7. ^ Zeitlmann L, Sirim P, Kremmer E, Kolanus W (Mar 2001). "Cloning of ACP33 as a novel intracellular ligand of CD4". J. Biol. Chem. 276 (12): 9123–32. PMID 11113139. doi:10.1074/jbc.M009270200. 
  8. ^ Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF (September 2010). "Pillars article: the CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes. 1988". J. Immunol. 185 (5): 2645–9. PMC 3791413Freely accessible. PMID 20724730. 
  9. ^ Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF (July 1988). "The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes". Proc. Natl. Acad. Sci. U.S.A. 85 (14): 5190–4. Bibcode:1988PNAS...85.5190R. PMC 281714Freely accessible. PMID 2455897. doi:10.1073/pnas.85.14.5190. 
  10. ^ Barber EK, Dasgupta JD, Schlossman SF, Trevillyan JM, Rudd CE (May 1989). "The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex". Proc. Natl. Acad. Sci. U.S.A. 86 (9): 3277–81. Bibcode:1989PNAS...86.3277B. PMC 287114Freely accessible. PMID 2470098. doi:10.1073/pnas.86.9.3277. 
  11. ^ Hawash IY, Hu XE, Adal A, Cassady JM, Geahlen RL, Harrison ML (April 2002). "The oxygen-substituted palmitic acid analogue, 13-oxypalmitic acid, inhibits Lck localization to lipid rafts and T cell signaling". Biochim. Biophys. Acta. 1589 (2): 140–50. PMID 12007789. doi:10.1016/S0167-4889(02)00165-9. 
  12. ^ Foti M, Phelouzat MA, Holm A, Rasmusson BJ, Carpentier JL (February 2002). "p56Lck anchors CD4 to distinct microdomains on microvilli". Proc. Natl. Acad. Sci. U.S.A. 99 (4): 2008–13. Bibcode:2002PNAS...99.2008F. PMC 122310Freely accessible. PMID 11854499. doi:10.1073/pnas.042689099. 
  13. ^ Gorska MM, Stafford SJ, Cen O, Sur S, Alam R (February 2004). "Unc119, a Novel Activator of Lck/Fyn, Is Essential for T Cell Activation". J. Exp. Med. 199 (3): 369–79. PMC 2211793Freely accessible. PMID 14757743. doi:10.1084/jem.20030589. 
  14. ^ Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA (June 1998). "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody". Nature. 393 (6686): 648–59. Bibcode:1998Natur.393..648K. PMID 9641677. doi:10.1038/31405. 
  15. ^ "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" (PDF). AIDSinfo. U.S. Department of Health & Human Services. 2013-02-13. 
  16. ^ Bofill M, Janossy G, Lee CA, MacDonald-Burns D, Phillips AN, Sabin C, Timms A, Johnson MA, Kernoff PB (May 1992). "Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis". Clin. Exp. Immunol. 88 (2): 243–52. PMC 1554313Freely accessible. PMID 1349272. doi:10.1111/j.1365-2249.1992.tb03068.x. 
  17. ^ a b c d e HIV Medicine Association (February 2016), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation, HIV Medicine Association, retrieved 9 May 2016 
  18. ^ Kumarasen Cooper; Anthony S-Y. Leong (2003). Manual of diagnostic antibodies for immunohistology. London: Greenwich Medical Media. p. 65. ISBN 1-84110-100-1. 
  19. ^ Zamani M, Tabatabaiefar MA, Mosayyebi S, Mashaghi A, Mansouri P (July 2010). "Possible association of the CD4 gene polymorphism with vitiligo in an Iranian population". Clin. Exp. Dermatol. 35 (5): 521–4. PMID 19843086. doi:10.1111/j.1365-2230.2009.03667.x. 
  20. ^ Ciccarelli F, De Martinis M, Ginaldi L (2014). "An update on autoinflammatory diseases". Curr. Med. Chem. 21 (3): 261–9. PMC 3905709Freely accessible. PMID 24164192. doi:10.2174/09298673113206660303. 
  21. ^ "550280 - BD Biosciences". BD Biosciences. Becton Dickinson. 

This article incorporates text from the public domain Pfam and InterPro IPR015274

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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

CD4, extracellular Provide feedback

Members of this family adopt an immunoglobulin-like beta-sandwich, with seven strands in 2 beta sheets, in a Greek key topology. They are predominantly found in the extracellular portion of CD4 proteins, where they enable interaction with major histocompatibility complex class II antigens [1].

Literature references

  1. Brady RL, Dodson EJ, Dodson GG, Lange G, Davis SJ, Williams AF, Barclay AN; , Science. 1993;260:979-983.: Crystal structure of domains 3 and 4 of rat CD4: relation to the NH2-terminal domains. PUBMED:8493535 EPMC:8493535

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This tab holds annotation information from the InterPro database.

InterPro entry IPR015274

This domain adopts an immunoglobulin-like beta-sandwich with seven strands in 2 beta sheets, in a Greek key topology. It is predominantly found in the extracellular portion of CD4 proteins, where it enables interaction with major histocompatibility complex class II antigens [PUBMED:8493535].

Domain organisation

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Seed source: pdb_1cid
Previous IDs: none
Type: Domain
Author: Sammut SJ
Number in seed: 20
Number in full: 74
Average length of the domain: 107.10 aa
Average identity of full alignment: 44 %
Average coverage of the sequence by the domain: 24.31 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 26.0 26.0
Trusted cut-off 26.2 26.0
Noise cut-off 25.9 25.9
Model length: 107
Family (HMM) version: 9
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Species distribution

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There are 3 interactions for this family. More...

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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CD4-extracel domain has been found. There are 15 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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