CD4

{{Infobox protein family

| Symbol = CD4-extrcel

| Name = CD4, Cluster of differentiation 4, extracellular

| image = PDB 1wip EBI.jpg

| width =

| caption = structure of T cell surface glycoprotein cd4, monoclinic crystal form

| Pfam = PF09191

| Pfam_clan =

| InterPro = IPR015274

| SMART =

| PROSITE =

| MEROPS =

| SCOP = 1cid

| TCDB =

| OPM family = 193

| OPM protein = 2klu

| CAZy =

| CDD = cd07695

| Membranome family =27

}}

File:CD4 correceptor.png

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.{{cite book |vauthors=Bernard A, Boumsell L, Hill C | chapter = Joint Report of the First International Workshop on Human Leucocyte Differentiation Antigens by the Investigators of the Participating Laboratories |veditors=Bernard A, Boumsell L, Dausset J, Milstein C, Schlossman SF | title = Leucocyte typing: human leucocyte differentiation antigens detected by monoclonal antibodies: specification, classification, nomenclature | quote = Report on the first international references workshop sponsored by INSERM, WHO and IUIS | publisher = Springer | location = Berlin | year = 1984 | pages = 45–48 | isbn = 0-387-12056-4 | doi = 10.1007/978-3-642-68857-7_3 }} In humans, the CD4 protein is encoded by the CD4 gene.{{cite journal | vauthors = Isobe M, Huebner K, Maddon PJ, Littman DR, Axel R, Croce CM | title = The gene encoding the T-cell surface protein T4 is located on human chromosome 12 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 12 | pages = 4399–4402 | date = June 1986 | pmid = 3086883 | pmc = 323740 | doi = 10.1073/pnas.83.12.4399 | doi-access = free | bibcode = 1986PNAS...83.4399I }}{{cite journal | vauthors = Ansari-Lari MA, Muzny DM, Lu J, Lu F, Lilley CE, Spanos S, Malley T, Gibbs RA | display-authors = 6 | title = A gene-rich cluster between the CD4 and triosephosphate isomerase genes at human chromosome 12p13 | journal = Genome Research | volume = 6 | issue = 4 | pages = 314–326 | date = April 1996 | pmid = 8723724 | doi = 10.1101/gr.6.4.314 | doi-access = free }}

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

File:CD4 receptor.png.]]

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.{{cite journal | vauthors = Brady RL, Dodson EJ, Dodson GG, Lange G, Davis SJ, Williams AF, Barclay AN | title = Crystal structure of domains 3 and 4 of rat CD4: relation to the NH2-terminal domains | journal = Science | volume = 260 | issue = 5110 | pages = 979–983 | date = May 1993 | pmid = 8493535 | doi = 10.1126/science.8493535 | bibcode = 1993Sci...260..979B }}

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.{{citation needed|date=June 2024}}

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.{{citation needed|date=June 2024}}

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{{cite journal | vauthors = Rudd CE, Trevillyan JM, Dasgupta JD, Wong LL, Schlossman SF | title = The CD4 receptor is complexed in detergent lysates to a protein-tyrosine kinase (pp58) from human T lymphocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 85 | issue = 14 | pages = 5190–5194 | date = July 1988 | pmid = 2455897 | pmc = 281714 | doi = 10.1073/pnas.85.14.5190 | doi-access = free | bibcode = 1988PNAS...85.5190R }} to phosphorylate tyrosine residues of immunoreceptor tyrosine activation motifs (ITAMs) on the cytoplasmic domains of CD3{{cite journal | vauthors = Barber EK, Dasgupta JD, Schlossman SF, Trevillyan JM, Rudd CE | title = The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 9 | pages = 3277–3281 | date = May 1989 | pmid = 2470098 | pmc = 287114 | doi = 10.1073/pnas.86.9.3277 | doi-access = free | bibcode = 1989PNAS...86.3277B }} 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.{{cite book | vauthors = Owens JA, Punt J, Stranford SA, Jones PP |title=Kuby Immunology |date=2013 |publisher=W.H. Freeman |location=New York |isbn=978-14641-3784-6 |pages=100–101 |edition=7th}}

File:CD4 and LAG-3 with opposing functions.png

CD4 is closely related to LAG-3,{{cite journal | vauthors = Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T | title = LAG-3, a novel lymphocyte activation gene closely related to CD4 | journal = The Journal of Experimental Medicine | volume = 171 | issue = 5 | pages = 1393–1405 | date = May 1990 | pmid = 1692078 | pmc = 2187904 | doi = 10.1084/jem.171.5.1393 }} and together they form an evolutionary conserved system from the level of sharks competing for binding Lck by conserved motifs in their cytoplasmic tails:{{cite journal | vauthors = Takizawa F, Hashimoto K, Miyazawa R, Ohta Y, Veríssimo A, Flajnik MF, Parra D, Tokunaga K, Suetake H, Sunyer JO, Dijkstra JM | display-authors = 6 | title = CD4 and LAG-3 from sharks to humans: related molecules with motifs for opposing functions | journal = Frontiers in Immunology | volume = 14 | pages = 1267743 | date = 2023-12-21 | pmid = 38187381 | pmc = 10768021 | doi = 10.3389/fimmu.2023.1267743 | doi-access = free }} CD4 through a Cys-X-Cys/His motif{{cite journal | vauthors = Kim PW, Sun ZY, Blacklow SC, Wagner G, Eck MJ | title = A zinc clasp structure tethers Lck to T cell coreceptors CD4 and CD8 | journal = Science | volume = 301 | issue = 5640 | pages = 1725–1728 | date = September 2003 | pmid = 14500983 | doi = 10.1126/science.1085643 | bibcode = 2003Sci...301.1725K | s2cid = 32336829 }} and LAG-3 through an immunoreceptor tyrosine-based inhibition motif like (ITIM-like) motif.{{cite journal | vauthors = Ohashi K, Takizawa F, Tokumaru N, Nakayasu C, Toda H, Fischer U, Moritomo T, Hashimoto K, Nakanishi T, Dijkstra JM | display-authors = 6 | title = 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 | journal = Immunogenetics | volume = 62 | issue = 8 | pages = 543–559 | date = August 2010 | pmid = 20614118 | doi = 10.1007/s00251-010-0460-1 | s2cid = 12282281 }}{{cite journal | vauthors = Maeda TK, Sugiura D, Okazaki IM, Maruhashi T, Okazaki T | title = Atypical motifs in the cytoplasmic region of the inhibitory immune co-receptor LAG-3 inhibit T cell activation | journal = The Journal of Biological Chemistry | volume = 294 | issue = 15 | pages = 6017–6026 | date = April 2019 | pmid = 30760527 | pmc = 6463702 | doi = 10.1074/jbc.RA119.007455 | doi-access = free }} 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,{{cite journal | vauthors = Zeitlmann L, Sirim P, Kremmer E, Kolanus W | title = Cloning of ACP33 as a novel intracellular ligand of CD4 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 12 | pages = 9123–9132 | date = March 2001 | pmid = 11113139 | doi = 10.1074/jbc.M009270200 | doi-access = free }} and Uncoordinated-119 (Unc-119).{{cite journal | vauthors = Gorska MM, Stafford SJ, Cen O, Sur S, Alam R | title = Unc119, a novel activator of Lck/Fyn, is essential for T cell activation | journal = The Journal of Experimental Medicine | volume = 199 | issue = 3 | pages = 369–379 | date = February 2004 | pmid = 14757743 | pmc = 2211793 | doi = 10.1084/jem.20030589 }}

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.{{cite journal | vauthors = Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA | title = Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody | journal = Nature | volume = 393 | issue = 6686 | pages = 648–659 | date = June 1998 | pmid = 9641677 | pmc = 5629912 | doi = 10.1038/31405 | bibcode = 1998Natur.393..648K }} 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|date=August 2016}}

National Institutes of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count{{cite web | url = http://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_37.pdf | title = Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents | work = AIDSinfo | publisher = U.S. Department of Health & Human Services | date = 2013-02-13 | access-date = 2013-10-24 | archive-date = 2013-10-29 | archive-url = https://web.archive.org/web/20131029192029/http://aidsinfo.nih.gov/contentfiles/lvguidelines/glchunk/glchunk_37.pdf | url-status = dead }} 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.{{cite journal | vauthors = Bofill M, Janossy G, Lee CA, MacDonald-Burns D, Phillips AN, Sabin C, Timms A, Johnson MA, Kernoff PB | display-authors = 6 | title = Laboratory control values for CD4 and CD8 T lymphocytes. Implications for HIV-1 diagnosis | journal = Clinical and Experimental Immunology | volume = 88 | issue = 2 | pages = 243–252 | date = May 1992 | pmid = 1349272 | pmc = 1554313 | doi = 10.1111/j.1365-2249.1992.tb03068.x }} 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|date=August 2016}}

Viral load testing provides more information about the efficacy for therapy than CD4 counts.{{Citation |author1 = HIV Medicine Association |author1-link = HIV Medicine Association |date = February 2016 |title = Five Things Physicians and Patients Should Question |publisher = HIV Medicine Association |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://www.choosingwisely.org/societies/hiv-medicine-association/ |access-date = 9 May 2016}} 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/mm³. If the count remains at 300–500/mm³, 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.

File:Reference ranges for blood tests - white blood cells.png 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.{{cite book | vauthors = Cooper K, Leong AS | title = Manual of diagnostic antibodies for immunohistology | publisher = Greenwich Medical Media | location = London | year = 2003 | pages = 65 | isbn = 1-84110-100-1 }} The antigen has also been associated with a number of autoimmune diseases such as vitiligo and type I diabetes mellitus.{{cite journal | vauthors = Zamani M, Tabatabaiefar MA, Mosayyebi S, Mashaghi A, Mansouri P | title = Possible association of the CD4 gene polymorphism with vitiligo in an Iranian population | journal = Clinical and Experimental Dermatology | volume = 35 | issue = 5 | pages = 521–524 | date = July 2010 | pmid = 19843086 | doi = 10.1111/j.1365-2230.2009.03667.x | s2cid = 10427963 }}

T-cells play a large part in autoinflammatory diseases.{{cite journal | vauthors = Ciccarelli F, De Martinis M, Ginaldi L | title = An update on autoinflammatory diseases | journal = Current Medicinal Chemistry | volume = 21 | issue = 3 | pages = 261–269 | year = 2014 | pmid = 24164192 | pmc = 3905709 | doi = 10.2174/09298673113206660303 }} 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).{{cite web|title=550280 – BD Biosciences|url=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|website=BD Biosciences|publisher=Becton Dickinson}}

References

External links

{{MeshName|CD1+Antigen}}
[https://web.archive.org/web/20110123180438/http://www.ebioscience.com/ebioscience/whatsnew/mousecdchart.htm Mouse CD Antigen Chart]
[http://www.ebioscience.com/ebioscience/whatsnew/humancdchart.htm Human CD Antigen Chart]
[http://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2005/Greendyke/gp120.htm Human Immunodeficiency Virus Glycoprotein 120]
{{UCSC gene info|CD4}}
{{PDBe-KB2|P01730|T-cell surface glycoprotein CD4}}

Category:Clusters of differentiation

Category:Glycoproteins

Category:Immunology

Category:Protein domains

Category:T cells

CD4