CD40 (protein)
Encyclopedia
CD40 is a costimulatory protein found on antigen presenting cells and is required for their activation. The binding of CD154
(CD40L) on TH cells
to CD40 activates antigen presenting cells and induces a variety of downstream effects.
Deficiency can cause Hyper-IgM syndrome type 3
.
formation. AT-hook
transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The TNFR-receptor associated factor adaptor proteins TRAF1
, TRAF2
, TRAF6
and possibly TRAF5
interact with this receptor and serve as mediators of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.
, the primary signal for activation is IFN-γ
from Th1 type CD4
T cell
s. The secondary signal is CD40L (CD154) on the T cell which binds CD40 on the macrophage
cell surface. As a result, the macrophage expresses more CD40 and TNF
receptors on its surface which helps increase the level of activation. The increase in activation results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species
and nitric oxide
, leading to the destruction of ingested microbe.
The B cell
can present antigens to helper T cells. If the T cell
recognizes the peptide presented by the B cell, the T cell synthesizes CD40L. The CD40L binds to the B cell's CD40 receptor which causes resting B cell activation. The T cell also produces IL-4 which directly binds to B cell receptors. As a result of this interaction, the B cell can undergo division, antibody
isotype switching, and differentiation to plasma cell
s. The end result is a B cell which is able to mass produce specific antibodies against an antigenic target.
The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including dendritic cells, B cells and macrophages. It can also be expressed by endothelial cells, smooth muscle cells, fibroblasts and epithelial cells. Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell haematopoiesis
(10)
with TRAF2
, TRAF3
, TRAF6
, TRAF5
and TTRAP
.
CD154
CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells , which leads to many effects depending on the target cell type...
(CD40L) on TH cells
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...
to CD40 activates antigen presenting cells and induces a variety of downstream effects.
Deficiency can cause Hyper-IgM syndrome type 3
Hyper-IgM syndrome type 3
Hyper-IgM syndrome type 3 is a form of Hyper IgM syndrome characterized by mutations of the CD40 gene. In this type, B cells cannot receive the signal from T cells to switch classes....
.
Function
The protein receptor encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal centerGerminal center
Germinal centers are sites within lymph nodes where mature B lymphocytes rapidly proliferate, differentiate, mutate their antibodies , and class switch their antibodies during a normal immune response to an infection...
formation. AT-hook
AT-hook
right|thumb|The second AT-hook of [[HMGA1]] bound to the minor-groove of AT-rich DNA. The amino-acid side chains and nucleotides have been hidden....
transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The TNFR-receptor associated factor adaptor proteins TRAF1
TRAF1
TNF receptor-associated factor 1 is a protein that in humans is encoded by the TRAF1 gene.-Interactions:TRAF1 has been shown to interact with CD30, CFLAR, Baculoviral IAP repeat-containing protein 3, BIRC2, Caspase 8, HIVEP3, TNFAIP3, TRAF2, RANK and TRAF interacting protein.-Further reading:...
, TRAF2
TRAF2
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.-Interactions:TRAF2 has been shown to interact with BCL10, CD30, CFLAR, IKK2, MAP3K7IP2, CD137, Caveolin 1, CD27, TNFRSF13B, TANK-binding kinase 1, TRAF1, CD40, UBE2N, MAP3K14, MAP4K2, CASP8AP2, HIVEP3,...
, TRAF6
TRAF6
TRAF6 is a TRAF human protein.-Interactions:TRAF6 has been shown to interact with SDCBP, IRAK2, IRAK1, MAP3K7IP2, MAP3K7IP1, TNFRSF13B, FHL2, CD40, IKBKG, RANK, HSPB2, UBE2N, SIGIRR, TAX1BP1, ASK1, PPP4C, TNFAIP3, Sequestosome 1, MAP3K7 and Ubiquitin C....
and possibly TRAF5
TRAF5
TNF receptor-associated factor 5 is a protein that in humans is encoded by the TRAF5 gene.-Interactions:TRAF5 has been shown to interact with ASK1, TNFRSF13B, CD134, CD30, CD40, RANK and TNFRSF14.-Further reading:...
interact with this receptor and serve as mediators of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.
Specific effects on cells
In the macrophageMacrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
, the primary signal for activation is IFN-γ
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
from Th1 type CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s. The secondary signal is CD40L (CD154) on the T cell which binds CD40 on the macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
cell surface. As a result, the macrophage expresses more CD40 and TNF
Tumor necrosis factors
Tumor necrosis factors refers to a group of cytokines family that can cause cell death . The first two members of the family to be identified were:...
receptors on its surface which helps increase the level of activation. The increase in activation results in the induction of potent microbicidal substances in the macrophage, including reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
and nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, leading to the destruction of ingested microbe.
The B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
can present antigens to helper T cells. If the T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
recognizes the peptide presented by the B cell, the T cell synthesizes CD40L. The CD40L binds to the B cell's CD40 receptor which causes resting B cell activation. The T cell also produces IL-4 which directly binds to B cell receptors. As a result of this interaction, the B cell can undergo division, antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
isotype switching, and differentiation to plasma cell
Plasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
s. The end result is a B cell which is able to mass produce specific antibodies against an antigenic target.
The expression of CD40 is diverse. CD40 is constitutively expressed by antigen presenting cells, including dendritic cells, B cells and macrophages. It can also be expressed by endothelial cells, smooth muscle cells, fibroblasts and epithelial cells. Consistent with its widespread expression on normal cells, CD40 is also expressed on a wide range of tumor cells, including non-Hodgkin's and Hodgkin's lymphomas, myeloma and some carcinomas including nasopharynx, bladder, cervix, kidney and ovary. CD40 is also expressed on B cell precursors in the bone marrow, and there is some evidence that CD40-CD154 interactions may play a role in the control of B cell haematopoiesis
Haematopoiesis
Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells...
(10)
Interactions
CD40 (protein) has 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 TRAF2
TRAF2
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.-Interactions:TRAF2 has been shown to interact with BCL10, CD30, CFLAR, IKK2, MAP3K7IP2, CD137, Caveolin 1, CD27, TNFRSF13B, TANK-binding kinase 1, TRAF1, CD40, UBE2N, MAP3K14, MAP4K2, CASP8AP2, HIVEP3,...
, TRAF3
TRAF3
TNF receptor-associated factor 3 is a protein that in humans is encoded by the TRAF3 gene.-Interactions:TRAF3 has been shown to interact with CD30, CD27, Lymphotoxin beta receptor, Nucleoporin 62, CD40, TNFSF14, RANK, Caspase 3 and TANK....
, TRAF6
TRAF6
TRAF6 is a TRAF human protein.-Interactions:TRAF6 has been shown to interact with SDCBP, IRAK2, IRAK1, MAP3K7IP2, MAP3K7IP1, TNFRSF13B, FHL2, CD40, IKBKG, RANK, HSPB2, UBE2N, SIGIRR, TAX1BP1, ASK1, PPP4C, TNFAIP3, Sequestosome 1, MAP3K7 and Ubiquitin C....
, TRAF5
TRAF5
TNF receptor-associated factor 5 is a protein that in humans is encoded by the TRAF5 gene.-Interactions:TRAF5 has been shown to interact with ASK1, TNFRSF13B, CD134, CD30, CD40, RANK and TNFRSF14.-Further reading:...
and TTRAP
TTRAP
TRAF and TNF receptor-associated protein is a protein that in humans is encoded by the TTRAP gene.-Interactions:TTRAP has been shown to interact with ETS1, TNFRSF1B and CD40.-Further reading:...
.