CD4

For other uses, see CD-4 (disambiguation).

CD4 molecule
Crystallographic structure of the V-set and C2 domains of human CD4.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1CDH, 1CDI, 1CDJ, 1CDU, 1CDY, 1G9M, 1G9N, 1GC1, 1JL4, 1OPN, 1OPT, 1OPW, 1Q68, 1RZJ, 1RZK, 1WBR, 1WIO, 1WIP, 1WIQ, 2B4C, 2JKR, 2JKT, 2KLU, 2NXY, 2NXZ, 2NY0, 2NY1, 2NY2, 2NY3, 2NY4, 2NY5, 2NY6, 2QAD, 3B71, 3CD4, 3JWD, 3JWO, 3LQA, 3O2D, 3S4S, 3S5L, 3T0E, 4H8W, 4JM2, 4P9H, 4Q6I, 4R2G, 4R4H, 4RQS
Identifiers
Symbols	CD4 ; CD4mut
External IDs	OMIM: 186940 MGI: 88335 HomoloGene: 513 ChEMBL: 2754 GeneCards: CD4 Gene
Gene ontology Molecular function • glycoprotein binding • receptor activity • transmembrane signaling receptor activity • extracellular matrix structural constituent • protein binding • zinc ion binding • coreceptor activity • enzyme binding • protein kinase binding • MHC class II protein binding • protein homodimerization activity Cellular component • early endosome • endoplasmic reticulum lumen • endoplasmic reticulum membrane • plasma membrane • external side of plasma membrane • integral component of membrane • T cell receptor complex • membrane raft Biological process • cytokine production • induction by virus of host cell-cell fusion • immune response • signal transduction • cell surface receptor signaling pathway • enzyme linked receptor protein signaling pathway • transmembrane receptor protein tyrosine kinase signaling pathway • viral process • T cell differentiation • entry into host cell • T cell costimulation • maintenance of protein location in cell • T cell selection • positive regulation of interleukin-2 biosynthetic process • innate immune response • protein palmitoleylation • positive regulation of protein kinase activity • regulation of defense response to virus by virus • positive regulation of peptidyl-tyrosine phosphorylation • defense response to Gram-negative bacterium • positive regulation of calcium-mediated signaling • T cell receptor signaling pathway • regulation of T cell activation Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	920	12504
Ensembl	ENSG00000010610	ENSMUSG00000023274
UniProt	P01730	P06332
RefSeq (mRNA)	NM_000616	NM_013488
RefSeq (protein)	NP_000607	NP_038516
Location (UCSC)	Chr 12: 6.79 – 6.82 Mb	Chr 6: 124.86 – 124.89 Mb
PubMed search	[1]	[2]

CD4, Cluster of differentiation 4, extracellular
structure of t-cell surface glycoprotein cd4, monoclinic crystal form
Identifiers
Symbol	CD4-extrcel
Pfam	PF09191
InterPro	IPR015274
SCOP	1cid
SUPERFAMILY	1cid
OPM superfamily	230
OPM protein	2klu
CDD	cd07695
Available protein structures: Pfam structures PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

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. 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

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.

Function

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.

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.

Other Interactions

CD4 has also been shown to interact with SPG21, Lck and Protein unc-119 homolog.

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. Normal blood values are usually expressed as the number of cells per microliter (or cubic millimeter, mm³) of blood, with normal values for CD4 cells being 500-1200 cells/mm³. 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. Patients often undergo treatments when the CD4 counts reach a level of 350 cells per microliter in Europe but usually around 500cpm in the US; people with less than 200 cells per microliter are at high risk of contracting AIDS defined illnesses. The newest National Institute of Health guidelines recommend treatment of any HIV-positive individuals, regardless of CD4 count Medical professionals also refer to CD4 tests to determine efficacy of treatment.

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. 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

External links

• CD1 Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)
• Mouse CD Antigen Chart
• Human CD Antigen Chart
• *Human Immunodeficiency Virus Glycoprotein 120

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