CD94/NKG2

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CD94/NKG2 is a family of C-type lectin receptors which are expressed predominantly on the surface of NK cells and a subset of CD8+ T-lymphocyte. [1] [2] These receptors stimulate or inhibit cytotoxic activity of NK cells, therefore they are divided into activating and inhibitory receptors according to their function. [3] CD94/NKG2 recognize nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse). [4]

Contents

CD94/NKG2 family

CD94/NKG2 family includes seven members: NKG2A, B, C, D, E, F and H. [5] Genes encoding these receptors are clustered in the natural killer complex (NKC) on human chromosome 12 and mouse chromosome 6 together with Clr (C-lectin related) genes. [6]

Structure

NKG2 receptors are transmembrane proteins type II which dimerize with CD94 molecule. CD94 contains a short cytoplasmic domain and it is responsible for signal transduction. Therefore NKG2 receptors form disulfide bonded heterodimers. NKG2D represent an exception, it is a homodimer. [7]

Signaling

Ligands

Receptors of CD94/NKG2 family bind nonclassical MHC glycoproteins class I (HLA-E in human and Qa-1 molecules in the mouse). [15]

Nonclassical MHC glycoproteins class I are structurally similar to classical MHC class I molecules, but they present mainly peptides derived from the signal peptides of MHC class I. Therefore NK cells can indirectly monitor the expression of classical MHC class I molecules through the interaction of CD94/NKG2 with HLA-E (Qa-1) and HLA-E (Qa-1) themselves as well. [16] During cytomegalovirus infection, virus peptides are presented on HLA-E and NK cells that express the CD94/NKG2C receptor can specifically recognise these virus peptides, which results in activation, expansion, and differentiation of adaptive NK cells. [17]

NKG2D constitutes an exception. Besides the fact that it is a homodimer, it associates with adaptor molecule DAP10 and its amino acid sequence is identical in only 28% in comparison with other CD94/NKG2 family members, NKG2D binds MHC class I homologues MIC-A (MHC class I polypeptide-related sequence A), [18] MIC-B and ULBP (UL-16 binding protein) [19] in human. MIC-A and MIC-B are expressed on the surface of epithelial and endothelial cells. The expression of these NKG2D ligands is higher in case of cellular stress, e.g. tumor disease or inflammation. This activates NK cells and triggers their cytotoxicity. [20] [21] ULBP is expressed constitutively in different tissues and it stimulates NK cells to secrete cytokines and chemokines. [22]

Mouse NKG2D binds H-60 molecules, five variants of Rae1 protein (Retinoic acid transcript 1) [23] and Mult1 (mouse ULBP-like transcript 1). [24] H-60 and Rae1 are structurally similar to MHC glycoproteins class I and their expression is increased in tumor cells. This leads to NK cell activation and IFN-γ production, which stimulates cells of innate immunity. [25]

See also

Related Research Articles

Natural killer cell type of cytotoxic lymphocyte critical to the innate immune system, providing rapid responses to viral-infected cells, acting at around 3 days after infection, and responding to tumor formation

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, acting at around 3 days after infection, and respond to tumor formation. Typically, immune cells detect the major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing the death of the infected cell by lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class 1. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Fc receptor

A Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

HLA-E protein-coding gene in the species Homo sapiens

HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the HLA-E gene. The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited polymorphism and a lower cell surface expression than its classical paralogues. The functional homolog in mice is called Qa-1b, officially known as H2-T23.

Killer-cell immunoglobulin-like receptors (KIRs), are a family of type I transmembrane glycoproteins expressed on the plasma membrane of natural killer (NK) cells and a minority of T cells. At least 15 genes and 2 pseudogenes encoding KIR map in a 150-kb region of the leukocyte receptor complex (LRC) on human chromosome 19q13.4 They regulate the killing function of these cells by interacting with major histocompatibility (MHC) class I molecules, which are expressed on all nucleated cell types. KIR receptors can distinguish between major histocompatibility (MHC) class I allelic variants, which allows them to detect virally infected cells or transformed cells. Most KIRs are inhibitory, meaning that their recognition of MHC molecules suppresses the cytotoxic activity of their NK cell. Only a limited number of KIRs are activating, meaning that their recognition of MHC molecules activates the cytotoxic activity of their cell. Initial expression of KIRs on NK cells is stochastic, but there is an educational process that NK cells undergo as they mature that alters the expression of KIRs to maximize the balance between effective defense and self-tolerance. As a result of KIR's role in killing unhealthy self-cells and not killing healthy self-cells, KIRs are involved in protection against and propensity to viral infection, autoimmune disease, and cancer. KIR molecules are highly polymorphic, meaning that their gene sequences differ greatly between individuals, and polygenic so that it is extremely rare for two unrelated individuals to possess the same KIR genotype.

KLRD1 mammalian protein found in Homo sapiens

CD94, also known as killer cell lectin-like receptor subfamily D, member 1 (KLRD1) is a human 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 receptors, but most of them are inhibitory. Inhibitory Ly49 receptors play 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.

NKG2 also known as CD159 is a receptor for natural killer cells. There are 7 NKG2 types: A, B, C, D, E, F and H. NKG2D is an activating receptor on the NK cell surface. NKG2A dimerizes with CD94 to make an inhibitory receptor (CD94/NKG2).

TYROBP protein-coding gene in the species Homo sapiens

TYRO protein tyrosine kinase-binding protein is an adapter protein that in humans is encoded by the TYROBP gene.

KIR2DL1 protein-coding gene in the species Homo sapiens

Killer cell immunoglobulin-like receptor 2DL1 is a protein that in humans is encoded by the KIR2DL1 gene.

KIR2DL4 protein-coding gene in the species Homo sapiens

Killer cell immunoglobulin-like receptor 2DL4 is a protein that in humans is encoded by the KIR2DL4 gene.

KLRC4 protein-coding gene in the species Homo sapiens

NKG2-F type II integral membrane protein is a protein that in humans is encoded by the KLRC4 gene.

KIR2DS4 protein-coding gene in the species Homo sapiens

Killer cell immunoglobulin-like receptor 2DS4 is a protein that in humans is encoded by the KIR2DS4 gene.

KLRC2 protein-coding gene in the species Homo sapiens

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).

HCST (gene) protein-coding gene in the species Homo sapiens

Hematopoietic cell signal transducer is a protein that in humans is encoded by the HCST gene.

ULBP2 protein-coding gene in the species Homo sapiens

UL16 binding protein 2 (ULBP2) is a cell surface glycoprotein encoded by ULBP2 gene located on the chromosome 6. ULBP2 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP2 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP2 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor. It functions as a stress-induced ligand for NKG2D receptor.

ULBP1 protein-coding gene in the species Homo sapiens

UL16 binding protein 1 (ULBP1) is a cell surface glycoprotein encoded by ULBP1 gene located on the chromosome 6. ULBP1 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP1 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP1 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor. It functions as a stress-induced ligand for NKG2D receptor. ULBP1 is, for example, upregulated during HCMV infection. Binding of HCMV-encoded UL16 glycoprotein to ULBP1 interferes with cell surface localization of ULBP1; this represents another mechanism by which HCMV-infected cells might escape the immune system.

ULBP3 protein-coding gene in the species Homo sapiens

UL16 binding protein 3 (ULBP3) is a cell surface glycoprotein encoded by ULBP3 gene located on the chromosome 6. ULBP3 is related to MHC class I molecules, but its gene maps outside the MHC locus. The domain structure of ULBP3 differs significantly from those of conventional MHC class I molecules. It does not contain the α3 domain and the transmembrane segment. ULBP3 is thus composed of only the α1α2 domain which is linked to the cell membrane by the GPI anchor. It functions as a stress-induced ligand for NKG2D receptor.

Killer activation receptor

Killer Activation Receptors (KARs) are receptors expressed on the plasmatic membrane of Natural Killer cells. KARs work together with inhibitory receptors, which inactivate them in order to regulate the NK cells functions on hosted or transformed cells. These two kinds of specific receptors have some morphological features in common, such as being transmembrane proteins. The similarities are specially found in the extracellular domains and, the differences tend to be in the intracellular domains. KARs and KIRs can have tyrosine containing activatory or inhibitory motifs in the intracellular part of the receptor molecule.

NKG2D protein-coding gene in the species Homo sapiens

NKG2D is a transmembrane protein belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 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.

Adaptive natural killer (NK) cells or memory-like NK cells is sub-population of differentiated specialized natural killer cells that have the potential to form immunological memory. Adaptive NK cells have been identified in both humans and mice. The term adaptive NK cells stems from their described immunological behaviour, which parallels functions of the adaptive immune system including dynamic expansions of defined subsets of cells and protective memory responses.

References

  1. ↑ Borrego F, Masilamani M, Marusina AI, Tang X, Coligan JE (2006), The CD94/NKG2 family of receptors: from molecules and cells to clinical relevance. Immunol Res. 35(3):263-78
  2. ↑ Colonna M, Moretta A, Vély F, Vivier E (2000), A high-resolution view of NK-cell receptors: structure and function. Immunol Today 21(9):428-31
  3. ↑ Yokoyama WM, Plougastel BF (2003), Immune functions encoded by the natural killer gene complex. Nat Rev Immunol. 3(4):304-16
  4. ↑ Lanier LL (2005), NK cell recognition. Annu Rev Immunol. 23:225-74
  5. ↑ Lanier LL (2005), NK cell recognition. Annu Rev Immunol. 23:225-74
  6. ↑ Colonna M, Moretta A, Vély F, Vivier E (2000), A high-resolution view of NK-cell receptors: structure and function. Immunol Today 21(9):428-31
  7. ↑ Lazetic S, Chang C, Houchins JP, Lanier LL, Phillips JH (1996), Human natural killer cell receptors involved in MHC class I recognition are disulfide-linked heterodimers of CD94 and NKG2 subunits. J Immunol. 157(11):4741-5
  8. ↑ Berg SF, Dissen E, Westgaard IH, Fossum S (1998), Two genes in the rat homologous to human NKG2. Eur J Immunol. 28(2):444-50
  9. ↑ Lanier LL (2008), Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 9(5):495-502
  10. ↑ Lanier LL (2008), Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 9(5):495-502
  11. ↑ Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C (May 2018). "Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells". Nature Immunology. 19 (5): 453–463. doi:10.1038/s41590-018-0082-6. PMID   29632329.
  12. ↑ Lanier LL (2008), Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol. 9(5):495-502
  13. ↑ Huang H, Wang X, Zhang Y, Zheng X, Wei H, Sun R (2010), Up-regulation of NKG2F receptor, a functionally unknown killer receptor, of human natural killer cells by interleukin-2 and interleukin-15. Oncol Rep. 24(4):1043-8
  14. ↑ Kim DK, Kabat J, Borrego F, Sanni TB, You CH, Coligan JE (2004), Human NKG2F is expressed and can associate with DAP12. Mol Immunol. 41(1):53-62
  15. ↑ Lanier LL (2005), NK cell recognition. Annu Rev Immunol. 23:225-74
  16. ↑ Yokoyama WM, Plougastel BF (2003), Immune functions encoded by the natural killer gene complex. Nat Rev Immunol. 3(4):304-16
  17. ↑ Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A, Durek P, Heinrich F, Gasparoni G, Babic M, Tomic A, Pietra G, Nienen M, Blau IW, Hofmann J, Na IK, Prinz I, Koenecke C, Hemmati P, Babel N, Arnold R, Walter J, Thurley K, Mashreghi MF, Messerle M, Romagnani C (May 2018). "Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells". Nature Immunology. 19 (5): 453–463. doi:10.1038/s41590-018-0082-6. PMID   29632329.
  18. ↑ Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999), Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MIC-A. Science 285(5428):727-9.
  19. ↑ Cosman D, Müllberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ (2001), ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity. 14(2):123-33.
  20. ↑ Bauer S, Groh V, Wu J, Steinle A, Phillips JH, Lanier LL, Spies T (1999), Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 285(5428):727-9.
  21. ↑ Cosman D, Müllberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ (2001), ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity. 14(2):123-33.
  22. ↑ Cosman D, Müllberg J, Sutherland CL, Chin W, Armitage R, Fanslow W, Kubin M, Chalupny NJ (2001), ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. Immunity. 14(2):123-33.
  23. ↑ Diefenbach A, Jamieson AM, Liu SD, Shastri N, Raulet DH (2000), Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol. 1(2):119-26.
  24. ↑ Carayannopoulos LN, Naidenko OV, Fremont DH, Yokoyama WM (2002), Cutting edge: murine UL16-binding protein-like transcript 1: a newly described transcript encoding a high-affinity ligand for murine NKG2D. J Immunol. 169(8):4079-83
  25. ↑ Diefenbach A, Jamieson AM, Liu SD, Shastri N, Raulet DH (2000), Ligands for the murine NKG2D receptor: expression by tumor cells and activation of NK cells and macrophages. Nat Immunol. 1(2):119-26.
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