CD244 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | CD244 , 2B4, NAIL, NKR2B4, Nmrk, SLAMF4, CD244 molecule | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 605554 MGI: 109294 HomoloGene: 9493 GeneCards: CD244 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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CD244 (Cluster of Differentiation 244) also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene. [5]
CD244 is a type-I transmembrane protein belonging to the signaling lymphocytic activation molecule family of receptors (SLAMF) which are expressed in different types of hematopoietic cells. [6] CD244 plays a role in the regulation of the immune system. [7]
A ligand of CD244 is CD48 (SLAMF2). CD48 also belongs to the SLAMF, it does not have an intracellular domain and it is anchored to the plasma membrane by a GPI-anchor. [6] Only these two receptors from the SLAMF mediate heterophilic interactions. [8] [7]
The receptor CD244 is encoded by the CD244 gene located on the long arm of human chromosome 1. [8] Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [9] CD244 was first described in NK cells but it is also expressed in monocytes, basophils, eosinophils, mast cells, dendritic cells, and T cells. [8] [10]
The receptor is composed of intracellular, transmembrane, and extracellular domains. The intracellular domain contains four intracellular tyrosine-based switch motives (ITSMs) and interacts with SH2 domain-containing proteins which are involved in the signaling and determine whether it will be activating or inhibitory. [9] [6] The extracellular region of the receptor is composed of one Ig variable-like domain and one Ig constant 2-like domain. [10] [6]
CD244 can function as an activating or inhibitory receptor. The expression and availability of an adaptor protein SAP determine whether the signal is activating or inhibitory. [9] The inhibitory signal is mediated by binding of phosphatases SHP1, SHP2, SHIP-1 or the kinase CsK on the third ITSM. [6] Activating signaling is associated with the adaptor protein SAP. [9] SAP binds to phosphorylated tyrosines in ITSMs. Then it binds to the kinase Fyn and that enhances downstream signaling. [11] Binding of EAT2 is associated with both the activating and the inhibitory signal. [9]
CD244 is expressed in all types of NK cells, [9] and it activates their cytotoxicity and IFNγ production. [9] [6] It is also expressed in a subset of effector and effector memory CD8+ T cells [9] where the activating signaling via CD244 enhances their proliferation and cytotoxic effect. [6]
NK cells and CD8+ T cells play a crucial role in antiviral immunity. The activating signaling via CD244 leads to the enhancement of their cytolytic activity that they use for killing infected cells. [7] The expression of CD244 is increased but the expression of SAP is decreased during some chronic viral infections, such as HIV, HBV and HCV, and that is associated with the inhibitory signal and the exhaustion of CD8+ T cells. [7] [9]
NK cells, T cells, dendritic cells, and myeloid-derived suppressor cells in the tumor microenvironment express CD244. [7] The type of the signal is determined by the ratio of expressed CD244 and adaptor protein SAP. However, inhibitory signaling has been shown to predominate in the tumor-associated immune cells. [10]
NK cells and CD8+ T cells use their cytolytic activity to kill tumor cells. Increased CD244 expression in these cells is associated with the inhibitory signal and the exhaustion of the cells. That leads to the impaired antitumor immunity caused by decreased cytotoxicity and proliferation of NK cells and CD8+ T cells. Dendritic cells are important antigen presenting cells. CD244 expression in dendritic cells is also associated with the inhibitory signal due to the low expression of SAP and therefore, they have decreased production of proinflammatory cytokines and reduced ability to activate NK cells and T cells. Myeloid-derived suppressor cells are suppressive cells also found in tumors. Their increased number in the tumor is associated with the progression of the disease. It is known that CD244 signaling in these cells enhances their immunosuppressive capacity resulting in the reduced immune response against tumors. [9]
In immunology, an immunological synapse is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T/B cell or Natural Killer cell. The interface was originally named after the neuronal synapse, with which it shares the main structural pattern. An immunological synapse consists of molecules involved in T cell activation, which compose typical patterns—activation clusters. Immunological synapses are the subject of much ongoing research.
Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.
Ly49 is a family of membrane C-type lectin-like receptors expressed mainly on NK cells but also on other immune cells. Their primary role is to bind MHC-I molecules to distinguish between self healthy cells and infected or altered cells. Ly49 family is coded by Klra gene cluster and include genes for both inhibitory and activating paired receptors, but most of them are inhibitory. Inhibitory Ly49 receptors play a role in the recognition of self cells and thus maintain self-tolerance and prevent autoimmunity by suppressing NK cell activation. On the other hand, activating receptors recognise ligands from cancer or viral infected cells and are used when cells lack or have abnormal expression of MHC-I molecules, which activate cytokine production and cytotoxic activity of NK and immune cells.
Leukocyte immunoglobulin-like receptor subfamily B member 1 is a protein that in humans is encoded by the LILRB1 gene.
SH2 domain–containing protein 1A is a protein that in humans is encoded by the SH2D1A gene. It is often called SLAM-associated protein, where "SLAM" refers to signaling lymphocytic activation molecules. It is a SH2 domain–containing molecule that plays a role in SLAM signaling. A putative function is as an adaptor for Fyn and competitor of phosphatases, leading to modulation of SLAM family function. SAP has been implicated in autoimmunity, and a mutation of it is associated with X-linked lymphoproliferative disease. At least 32 disease-causing mutations in this gene have been discovered.
CD48 antigen also known as B-lymphocyte activation marker (BLAST-1) or signaling lymphocytic activation molecule 2 (SLAMF2) is a protein that in humans is encoded by the CD48 gene.
Killer cell immunoglobulin-like receptor 2DL4 is a protein that in humans is encoded by the KIR2DL4 gene.
CD84 is a human protein encoded by the CD84 gene.
CD226, PTA1 or DNAM-1 is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.
Killer cell lectin-like receptor subfamily B, member 1, also known as KLRB1, NKR-P1A or CD161, is a human gene.
SLAM family member 6 is a protein that in humans is encoded by the SLAMF6 gene.
NKG2-C type II integral membrane protein or NKG2C is a protein that in humans is encoded by the KLRC2 gene. It is also known as or cluster of differentiation 159c (CD159c).
Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biologic effects on T cell function. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
SLAM family member 7 is a protein that in humans is encoded by the SLAMF7 gene.
B- and T-lymphocyte attenuator or BTLA is a protein that belongs to the CD28 immunoglobulin superfamily (IgSF) which is encoded by the BTLA gene located on the 3rd human chromosome. BTLA was first discovered in 2003 as an inhibitor of Th1 expansion and it became the 3rd member of the CD28 IgSF. However, its discovered ligand herpes virus entry mediator or HVEM belongs to the tumor necrosis factor receptor superfamily (TNFRSF). This finding was surprising because until the discovery of HVEM it was believed that receptors and ligands always belong to the same family.
Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells. HAVCR2 receptor is a regulator of the immune response.
Killer cell lectin-like receptor subfamily G member 1 is a protein that in humans is encoded by the KLRG1 gene.
Signaling lymphocytic activation molecule (SLAM) is a family of genes. Homophilic binding between SLAMs is involved in cell-to-cell adhesion during antigen presentation.
NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.
Paired receptors are pairs or clusters of receptor proteins that bind to extracellular ligands but have opposing activating and inhibitory signaling effects. Traditionally, paired receptors are defined as homologous pairs with similar extracellular domains and different cytoplasmic regions, whose genes are located together in the genome as part of the same gene cluster and which evolved through gene duplication. Homologous paired receptors often, but not always, have a shared ligand in common. More broadly, pairs of receptors have been identified that exhibit paired functional behavior - responding to a shared ligand with opposing intracellular signals - but are not closely homologous or co-located in the genome. Paired receptors are highly expressed in the cells of the immune system, especially natural killer (NK) and myeloid cells, and are involved in immune regulation.