CD4
Encyclopedia
CD4 is a glycoprotein
expressed on the surface of T helper cell
s, 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
.
.
It has four immunoglobulin domains (D1 to D4) that are exposed on the extracellular surface of the cell:
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).
The short cytoplasmic/intracellular
tail (C) of CD4 contains a special sequence of amino acids that allow it to interact with the lck molecule described above.
that assists the T cell receptor
(TCR) with an antigen-presenting cell
. Using its portion that resides inside the T cell, CD4 amplifies the signal generated by the TCR by recruiting an enzyme
, known as the tyrosine kinase
lck
, which is essential for activating many molecules involved in the signaling cascade of an activated T cell. 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.
with SPG21
, Lck
and Protein unc-119 homolog
.
protein known as gp120
to CD4. 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
, which of these co-receptor is used during infection is dependent on whether the virus is infecting a macrophage or T-helper cell . 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
.
test e.g. does not check the presence of viral DNA, or specific antibodies against HIV, the CD4 count is used to assess the immune system of patients. Patients often undergo treatments when the CD4 count reach a level of 350 cells per microliter; less than 200 cells per microliter in an HIV positive individual is diagnosed as AIDS
. Medical professionals also refer to CD4 tests to determine efficacy of treatment.
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.
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
expressed on the surface of T helper cell
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...
s, 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
Monoclonal antibodies
Monoclonal antibodies are monospecific antibodies that are the same because they are made by identical immune cells that are all clones of a unique parent cell....
that reacted with it) before being named CD4 in 1984. In humans, the CD4 protein is encoded by the CD4 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Structure
Like many cell surface receptors/markers, CD4 is a member of the immunoglobulin superfamilyImmunoglobulin superfamily
The immunoglobulin superfamily is a large group of cell surface and soluble proteins that are involved in the recognition, binding, or adhesion processes of cells. Molecules are categorized as members of this superfamily based on shared structural features with immunoglobulins ; they all possess a...
.
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
CD8
CD8 is a transmembrane glycoprotein that serves as a co-receptor for the T cell receptor . Like the TCR, CD8 binds to a major histocompatibility complex molecule, but is specific for the class I MHC protein. There are two isoforms of the protein, alpha and beta, each encoded by a different gene...
) on their surface, therefore, are specific for antigens presented by MHC II and not by MHC class I
MHC class I
MHC class I molecules are one of two primary classes of major histocompatibility complex molecules and are found on every nucleated cell of the body...
(they are MHC class II-restricted).
The short cytoplasmic/intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
tail (C) of CD4 contains a special sequence of amino acids that allow it to interact with the lck molecule described above.
Function
CD4 is a co-receptorCo-receptor
A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.-Co-receptor Properties:...
that assists the T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
(TCR) with an antigen-presenting cell
Antigen-presenting cell
An antigen-presenting cell or accessory cell is a cell that displays foreign antigen complexes with major histocompatibility complex on their surfaces. T-cells may recognize these complexes using their T-cell receptors...
. Using its portion that resides inside the T cell, CD4 amplifies the signal generated by the TCR by recruiting an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, known as the tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
lck
Lck
Lck is a protein that is found inside specialized cells of the immune system called lymphocytes. Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes...
, which is essential for activating many molecules involved in the signaling cascade of an activated T cell. CD4 also interacts directly with MHC class II
MHC class II
MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells and B cells, all of which are professional antigen-presenting cells ....
molecules on the surface of the antigen-presenting cell using its extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
domain. The extracellular domain adopts an immunoglobulin-like beta-sandwich with seven strands in 2 beta sheets, in a Greek key topology.
Other Interactions
CD4 has also been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with SPG21
SPG21
Maspardin is a protein that in humans is encoded by the SPG21 gene.-Further reading:...
, Lck
Lck
Lck is a protein that is found inside specialized cells of the immune system called lymphocytes. Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes...
and Protein unc-119 homolog
Protein unc-119 homolog
Protein unc-119 homolog A is a protein that in humans is encoded by the UNC119 gene.-Interactions:Protein unc-119 homolog has been shown to interact with Lck, ARL3, ARL2, LYN, Interleukin 5 receptor alpha subunit, CD247, CD4 and FYN....
.
HIV infection
HIV-1 uses CD4 to gain entry into host T-cells and achieves this by binding of the viral envelopeViral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...
protein known as gp120
Gp120
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
to CD4. 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
CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
or CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
, which of these co-receptor is used during infection is dependent on whether the virus is infecting a macrophage or T-helper cell . Following a structural change in another viral protein (gp41
Gp41
gp41 is a subunit of the envelope protein complex of retroviruses, including Human immunodeficiency virus and Simian-Human immunodeficiency virus. This glycoprotein subunit remains non-covalently-bound to gp120, and provides the second step by which HIV enters the cell...
), HIV inserts a fusion peptide into the host cell that allows the outer membrane of the virus to fuse with the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
.
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 500-1200x10-6/L. CD4 count test measures the number of T cells expressing CD4. Results are usually expressed in the number of cells per microliter (or cubic millimeter, mm3) of blood. While CD4 tests are not a direct HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
test e.g. does not check the presence of viral DNA, or specific antibodies against HIV, the CD4 count is used to assess the immune system of patients. Patients often undergo treatments when the CD4 count reach a level of 350 cells per microliter; less than 200 cells per microliter in an HIV positive individual is diagnosed as AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
. Medical professionals also refer to CD4 tests to determine efficacy of treatment.
Other diseases
CD4 continues to be expressed in most neoplasms derived from T helper cells. It is therefore possible to use CD4 immunohistochemistryImmunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
on tissue biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
samples to identify most forms of peripheral T cell lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
and related malignant conditions. The antigen has also been associated with a number of autoimmune diseases
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
such as vitiligo
Vitiligo
Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
and type I diabetes mellitus.