CD4
| CD4, Cluster of differentiation 4, extracellular | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| OPM superfamily | 193 | ||||||||
| OPM protein | 2klu | ||||||||
| CDD | cd07695 | ||||||||
| Membranome | 27 | ||||||||
| |||||||||
In
monoclonal antibody that reacted with it) before being named CD4 in 1984.[5] In humans, the CD4 protein is encoded by the CD4 gene.[6][7]
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 immunoglobulinvariable (IgV) domains.
- D2 and D4 resemble immunoglobulinconstant (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.[8]
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
amino acids that allow it to recruit and interact with the tyrosine kinase Lck
.
Function
CD4 is a
immunoreceptor tyrosine activation motifs (ITAMs) on the cytoplasmic domains of CD3[10] 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.[11]
CD4 is closely related to
LAG-3,[12] and together they form an evolutionary conserved system from the level of sharks competing for binding Lck by conserved motifs in their cytoplasmic tails:[13] CD4 through a Cys-X-Cys/His motif[14] and LAG-3 through an immunoreceptor tyrosine-based inhibition motif like (ITIM-like) motif.[13][15][16]
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
Disease
HIV infection
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
]
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.[21] 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.[22] For the first 2 years of HIV therapy, CD4 counts may be done every 3–6 months.[22] 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.[22] If the count remains at 300–500/mm3, then the tests can be done annually.[22] It is not necessary to schedule CD4 counts with viral load tests and the two should be done independently when each is indicated.[22]
Other diseases
CD4 continues to be expressed in most
type I diabetes mellitus.[24]
T-cells play a large part in autoinflammatory diseases.[25] 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).[26]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000010610 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000023274 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ISBN 0-387-12056-4.
Report on the first international references workshop sponsored by INSERM, WHO and IUIS
- PMID 3086883.
- PMID 8723724.
- PMID 8493535.
- PMID 2455897.
- PMID 2470098.
- ISBN 978-14641-3784-6.
- PMID 1692078.
- ^ PMID 38187381.
- S2CID 32336829.
- S2CID 12282281.
- PMID 30760527.
- PMID 11113139.
- PMID 14757743.
- PMID 9641677.
- ^ "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. Archived from the original (PDF) on 2013-10-29. Retrieved 2013-10-24.
- PMID 1349272.
- ^ ABIM Foundation, HIV Medicine Association, retrieved 9 May 2016
- ISBN 1-84110-100-1.
- S2CID 10427963.
- PMID 24164192.
- ^ "550280 – BD Biosciences". BD Biosciences. Becton Dickinson.
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. PMID 8512039.
- Geyer M, Fackler OT, Peterlin BM (July 2001). "Structure--function relationships in HIV-1 Nef". EMBO Reports. 2 (7): 580–585. 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. 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. 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. 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. 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. 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. PMID 15638726.
- Anderson JL, Hope TJ (April 2004). "HIV accessory proteins and surviving the host cell". Current HIV/AIDS Reports. 1 (1): 47–53. 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. PMID 16354571.
- Stove V, Verhasselt B (January 2006). "Modelling thymic HIV-1 Nef effects". Current HIV Research. 4 (1): 57–64. 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.
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