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An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of 
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
s that is found intracellularly in the
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
ic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family found on immune cells. These immune cells include
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s,
B cell B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
s, NK cells,
dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
s,
macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s and
mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a p ...
s.  ITIMs have similar structures of S/I/V/LxYxxI/V/L, where x is any amino acid, Y is a
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a conditionally essential amino acid with a polar side group. The word "tyrosine" is ...
residue that can be phosphorylated, S is the amino acid
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...
, I is the amino acid
isoleucine Isoleucine (symbol Ile or I) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid group (which is in the depro ...
, and V is the amino acid
valine Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deproton ...
. ITIMs recruit SH2 domain-containing
phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
s, which inhibit cellular activation. ITIM-containing receptors often serve to target immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in regulation of immune system allowing negative regulation at different levels of the
immune response An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellula ...
. A list of human candidate ITIM-containing proteins has been generated by proteome-wide scans. It has included more than 135 proteins with ITIM motif. This list is reportedly expanded by studying rare human SNPs that create the consensus signature S/I/V/LxYxxI/V/L motif.


Structure

ITIM motifs are defined as six amino acid signature with the consensus sequence S/I/V/LxYxxL/V, where x stands for any
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
, Y for a tyrosine residue that can be phosphorylated and S, I, V for amino acids serine, isoleucine, and valine, respectively. ITIM conserved sequence was first identified in the low affinity IgG receptor FcγRIIB. All ITIM containing receptors are a part of the
immunoglobulin superfamily The immunoglobulin superfamily (IgSF) is a large protein superfamily 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 ...
.


Signaling by ITIM

The main characteristic of ITIM-containing molecules is that they become tyrosyl-phosphorylated. In order to become phosphorylated, the inhibitory receptor has to be brought in close proximity to the
kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
. This may be achieved by co- crosslinking with an ITAM motif of activating receptor that recruits a
Src family kinase Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src (gene), Src, YES1, Yes, FYN, Fyn, and FGR (gene), Fgr, forming the SrcA subfamily, Lck, HCK, Hck, Tyrosine-protein kinase BLK, Blk, and Lyn (Src fam ...
. ITIMs place phosphatases near ITAM-containing receptors, allowing phosphatases to dephosphorylate. This results in the deactivation of the signaling pathway of the ITAM-related receptor. Ligand independent phosphorylation of ITIM-bearing molecules may also occur. Phosphorylated ITIM molecules then recruit SH2 domain-containing phosphatases. Four SH2 domain-containing phosphatases have been identified: the two lipid phosphatases SHIP1 and SHIP2 and the two protein tyrosine phosphatases (PTPs) SHP-1 and SHP-2. The dephosphorylation of cell activation critical substrates results due to phosphorylated ITIM's serving as recruitment sites for SHP-1 and SHP-2. The vast majority of ITIM-containing receptors were found to recruit either SHIPs or SHPs. These phosphatases inhibit activation of molecules involved in cell signaling, most commonly by binding to activating receptors including TCRs, BCRs and FcRs. Subsequently, phospholipase Cy and phosphatidylinositol 3-kinase (PLCy and PI3-K) are activated, together leading to the production of phosphoinositol messengers and increase in cytoplasmic Ca2+.


SHIP

Several ITIM-bearing receptors bind SHIP, including FcγRIIB. SHIP is a 5′ inositol phosphatase that is expressed in most
hematopoietic Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
cells. It plays an important regulatory role in the immune system. SHIP consists of an N-terminal SH2 domain, a catalytic domain and a C-terminal tail that contains two phosphorylation sites. There are several isoforms of SHIP and the expression of these isoforms differs among different cell types. In addition, another SHIP gene, SHIP-2, has been identified. SHIP-2 is also expressed in non-hematopoietic cells. The binding of SHIP to ITIM-bearing receptors is mediated by the SH2 domain. There are several mechanisms by which SHIP can inhibit cell activation. These can be divided into mechanisms that involve the catalytic activity of SHIP and mechanisms that involve interactions of other molecules with the C-terminal part of SHIP.


SHP

Many ITIM-bearing receptors recruit SHP-1 and/or SHP-2 including KIRs, ILT, Ly49, LAIR-1,
CD22 CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule tha ...
, CD72 and Signal Regulatory Protein SIRPα. SHP-1 and SHP-2 are structurally related protein tyrosine phosphatases but have different expression patterns and biological functions. SHP-1 is expressed in hematopoietic cells and at lower levels in
epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
. Like SHIP, SHP-1 is involved in the negative regulation of cell activation following a variety of stimuli such as growth factors, cytokines, integrin signaling and antigen receptor signaling. SHP-2 is ubiquitously expressed and is considered a positive regulator of cytokine and growth factor receptor signaling. SHP-1 and SHP-2 consist of two SH-2 domains, a catalytic domain and a C-terminal tail. The N-terminal SH2 domain is involved in an auto-inhibitory mechanism, as removal of this domain activates the phosphatase. Recruitment of either SHIP or SHP-1 by ITIM-bearing receptors has different outcomes: recruitment of SHP-1 abrogates tyrosine phosphorylation of signaling molecules that would occur upon triggering of an ITAM-bearing receptor, while SHIP recruitment does not affect the initial phosphorylation, but interferes with the recruitment of downstream effectors to the site of cell activation. ITIMs can also work in conjunction with immunoreceptor tyrosine-based switch motifs (ITSM) in order to activate ITIM-bearing receptors such as SHP-2.


Negative vs. positive signaling

Even if the most receptors containing ITIM are considered to have inhibitory effects on signaling pathways of immune response, the function of SIRPα, CD22 and also PECAM-1, which is expressed on immune cells and endothelium and is involved in many signaling pathways, show that not all so called ITIM-bearing receptors can be considered to be inhibitory receptors. Several other proteins that are usually considered as stimulatory receptors contain ITIM-like sequences, e.g. IL-4. In contrast, the activating NK cell receptor NKp44 contains an ITIM, but this seems to be non-functional.


Inhibitory receptors bearing ITIM

Some of the important receptors bearing ITIM motifs are listed in the table below: ''My, myeloid; Hm, hematopoietic; NK, natural killer; EC, epithelial cells; DC, dendritic cells.'' (Modified according to)


In immunotherapy

On the basis of the inhibitory effects of FcγRIIB, a lot of prototypic molecules was constructed and used for developing new therapeutic approaches of allergies. A genetically engineered molecule consisting of a human IgG1 Fc fragment fused to a human IgE Fc fragment was first reported to inhibit IgE-induced human mast cell and basophil activation. In selected human malignancies such as acute myeloid leukemia, allogeneic hematopoietic cell transplantations have shown that the development of donor NK cells in recipient patients lacking donor KIR ligands can lead to improved engraftment and post-transplant survival by boosting graft-versus-leukemia effect in the absence of
graft-versus-host disease Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which rema ...
.


References

{{reflist Immune system