Biology:CD4

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Short description: Marker on immune cells


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example
CD4, Cluster of differentiation 4, extracellular
PDB 1wip EBI.jpg
structure of t-cell surface glycoprotein cd4, monoclinic crystal form
Identifiers
SymbolCD4-extrcel
PfamPF09191
InterProIPR015274
SCOP21cid / SCOPe / SUPFAM
OPM superfamily193
OPM protein2klu
CDDcd07695
Membranome27
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 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.[1] In humans, the CD4 protein is encoded by the CD4 gene.[2][3]

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

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.

The immunoglobulin variable (IgV) domain of D1 adopts an immunoglobulin-like β-sandwich fold with seven β-strands in 2 β-sheets, in a Greek key topology.[4]

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[5] to phosphorylate tyrosine residues of immunoreceptor tyrosine activation motifs (ITAMs) on the cytoplasmic domains of CD3[6] 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.[7]

Conservation of their respective cytoplasmic tail motifs, CxC/H in the case of CD4 and an ITIM-like motif in the case of LAG-3, supports that competition between CD4 and LAG-3 for binding of kinase LCK is a conserved core part of the jawed vertebrate immune system.

CD4 is closely related to LAG-3,[8] and together they form an evolutionary conserved system from the level of sharks competing for binding Lck by conserved motifs in their cytoplasmic tails:[9] CD4 through a Cys-X-Cys/His motif[10] and LAG-3 through an immunoreceptor tyrosine-based inhibition motif like (ITIM-like) motif.[9][11][12] 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,[13] and Uncoordinated-119 (Unc-119).[14]

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.[15] 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[16] 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.[17] 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.[18] For the first 2 years of HIV therapy, CD4 counts may be done every 3–6 months.[18] 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.[18] If the count remains at 300–500/mm3, then the tests can be done annually.[18] It is not necessary to schedule CD4 counts with viral load tests and the two should be done independently when each is indicated.[18]

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.[19] The antigen has also been associated with a number of autoimmune diseases such as vitiligo and type I diabetes mellitus.[20]

T-cells play a large part in autoinflammatory diseases.[21] 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).[22]

See also

References

  1. ↑ "Joint Report of the First International Workshop on Human Leucocyte Differentiation Antigens by the Investigators of the Participating Laboratories". Leucocyte typing: human leucocyte differentiation antigens detected by monoclonal antibodies: specification, classification, nomenclature. Berlin: Springer. 1984. pp. 45–48. doi:10.1007/978-3-642-68857-7_3. ISBN 0-387-12056-4. "Report on the first international references workshop sponsored by INSERM, WHO and IUIS" 
  2. ↑ "The gene encoding the T-cell surface protein T4 is located on human chromosome 12". Proceedings of the National Academy of Sciences of the United States of America 83 (12): 4399–4402. June 1986. doi:10.1073/pnas.83.12.4399. PMID 3086883. Bibcode: 1986PNAS...83.4399I. 
  3. ↑ "A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13". Genome Research 6 (4): 314–326. April 1996. doi:10.1101/gr.6.4.314. PMID 8723724. 
  4. ↑ "Crystal structure of domains 3 and 4 of rat CD4: relation to the NH2-terminal domains". Science 260 (5110): 979–983. May 1993. doi:10.1126/science.8493535. PMID 8493535. Bibcode: 1993Sci...260..979B. 
  5. ↑ "The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes". Proceedings of the National Academy of Sciences of the United States of America 85 (14): 5190–5194. July 1988. doi:10.1073/pnas.85.14.5190. PMID 2455897. Bibcode: 1988PNAS...85.5190R. 
  6. ↑ "The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex". Proceedings of the National Academy of Sciences of the United States of America 86 (9): 3277–3281. May 1989. doi:10.1073/pnas.86.9.3277. PMID 2470098. Bibcode: 1989PNAS...86.3277B. 
  7. ↑ Kuby Immunology (7th ed.). New York: W.H. Freeman. 2013. pp. 100–101. ISBN 978-14641-3784-6. 
  8. ↑ "LAG-3, a novel lymphocyte activation gene closely related to CD4". The Journal of Experimental Medicine 171 (5): 1393–1405. May 1990. doi:10.1084/jem.171.5.1393. PMID 1692078. 
  9. ↑ 9.0 9.1 "CD4 and LAG-3 from sharks to humans: related molecules with motifs for opposing functions". Frontiers in Immunology 14: 1267743. 2023-12-21. doi:10.3389/fimmu.2023.1267743. PMID 38187381. 
  10. ↑ "A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8". Science 301 (5640): 1725–1728. September 2003. doi:10.1126/science.1085643. PMID 14500983. Bibcode: 2003Sci...301.1725K. 
  11. ↑ "A molecule in teleost fish, related with human MHC-encoded G6F, has a cytoplasmic tail with ITAM and marks the surface of thrombocytes and in some fishes also of erythrocytes". Immunogenetics 62 (8): 543–559. August 2010. doi:10.1007/s00251-010-0460-1. PMID 20614118. 
  12. ↑ "Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation". The Journal of Biological Chemistry 294 (15): 6017–6026. April 2019. doi:10.1074/jbc.RA119.007455. PMID 30760527. 
  13. ↑ "Cloning of ACP33 as a novel intracellular ligand of CD4". The Journal of Biological Chemistry 276 (12): 9123–9132. March 2001. doi:10.1074/jbc.M009270200. PMID 11113139. 
  14. ↑ "Unc119, a novel activator of Lck/Fyn, is essential for T cell activation". The Journal of Experimental Medicine 199 (3): 369–379. February 2004. doi:10.1084/jem.20030589. PMID 14757743. 
  15. ↑ "Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody". Nature 393 (6686): 648–659. June 1998. doi:10.1038/31405. PMID 9641677. Bibcode: 1998Natur.393..648K. 
  16. ↑ "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents". AIDSinfo. U.S. Department of Health & Human Services. 2013-02-13. http://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_37.pdf. 
  17. ↑ "Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis". Clinical and Experimental Immunology 88 (2): 243–252. May 1992. doi:10.1111/j.1365-2249.1992.tb03068.x. PMID 1349272. 
  18. ↑ 18.0 18.1 18.2 18.3 18.4 HIV Medicine Association (February 2016), "Five Things Physicians and Patients Should Question", Choosing Wisely: an initiative of the ABIM Foundation (HIV Medicine Association), http://www.choosingwisely.org/societies/hiv-medicine-association/, retrieved 9 May 2016 
  19. ↑ Manual of diagnostic antibodies for immunohistology. London: Greenwich Medical Media. 2003. pp. 65. ISBN 1-84110-100-1. 
  20. ↑ "Possible association of the CD4 gene polymorphism with vitiligo in an Iranian population". Clinical and Experimental Dermatology 35 (5): 521–524. July 2010. doi:10.1111/j.1365-2230.2009.03667.x. PMID 19843086. 
  21. ↑ "An update on autoinflammatory diseases". Current Medicinal Chemistry 21 (3): 261–269. 2014. doi:10.2174/09298673113206660303. PMID 24164192. 
  22. ↑ "550280 – BD Biosciences". Becton Dickinson. http://www.bdbiosciences.com/us/reagents/research/antibodies-buffers/immunology-reagents/anti-mouse-antibodies/cell-surface-antigens/purified-rat-anti-mouse-cd4-rm4-5/p/550280. 

Further reading

External links

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



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