CD4



In is_associated_with::molecular biology, CD4 (is_associated_with::cluster of differentiation 4) is a is_associated_with::glycoprotein found on the surface of immune cells such as is_associated_with::T helper cells, is_associated_with::monocytes, is_associated_with::macrophages, and is_associated_with::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 is_associated_with::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
Like many cell surface receptors/markers, CD4 is a member of the is_associated_with::immunoglobulin superfamily.

It has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell:
 * D1 and D3 resemble is_associated_with::immunoglobulin variable (IgV) domains.
 * D2 and D4 resemble immunoglobulin constant (IgC) domains.

CD4 uses its D1 domain to interact with the β2-domain of is_associated_with::MHC class II molecules. T cells expressing CD4 molecules (and not is_associated_with::CD8) on their surface, therefore, are specific for antigens presented by MHC II and not by is_associated_with::MHC class I (they are MHC class II-restricted). MHC class I contains is_associated_with::Beta-2 microglobulin.

The short is_associated_with::cytoplasmic/is_associated_with::intracellular tail (C) of CD4 contains a special sequence of is_associated_with::amino acids that allow it to interact with the is_associated_with::lck molecule.

Function
CD4 is a is_associated_with::co-receptor that assists the is_associated_with::T cell receptor (TCR) in communicating with an is_associated_with::antigen-presenting cell. Using its intracellular domain, CD4 amplifies the signal generated by the TCR by recruiting an is_associated_with::enzyme, the is_associated_with::tyrosine kinase is_associated_with::Lck, which is essential for activating many molecular components of the signaling cascade of an activated T cell. Various types of is_associated_with::T helper cells are thereby produced. CD4 also interacts directly with is_associated_with::MHC class II molecules on the surface of the antigen-presenting cell using its is_associated_with::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 is_associated_with::SPG21, is_associated_with::Lck    and is_associated_with::Protein unc-119 homolog.

HIV infection
is_associated_with::HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its is_associated_with::viral envelope protein known as is_associated_with::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 is_associated_with::chemokine receptors is_associated_with::CCR5 or is_associated_with::CXCR4. Following a structural change in another viral protein (is_associated_with::gp41), HIV inserts a is_associated_with::fusion peptide into the host cell that allows the outer membrane of the virus to fuse with the is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::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.



Other diseases
CD4 continues to be expressed in most is_associated_with::neoplasms derived from is_associated_with::T helper cells. It is therefore possible to use CD4 is_associated_with::immunohistochemistry on tissue is_associated_with::biopsy samples to identify most forms of peripheral T cell is_associated_with::lymphoma and related malignant conditions. The antigen has also been associated with a number of autoimmune diseases such as is_associated_with::vitiligo and is_associated_with::type I diabetes mellitus.