Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q29983 (MIC)
 21,138 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

NKG2D is an activating receptor that stimulates innate immune responses by natural killer cells upon engagement by MIC ligands, which are induced by cellular stress. Because NKG2D is also present on most CD8alphabeta T cells, it may modulate antigen-specific T cell responses, depending on whether MIC molecules--distant homologs of major histocompatibility complex (MHC) class I with no function in antigen presentation--are induced on the surface of pathogen-infected cells. We found that infection by cytomegalovirus (CMV) resulted in substantial increases in MIC on cultured fibroblast and endothelial cells and was associated with induced MIC expression in interstitial pneumonia. MIC engagement of NKG2D potently augmented T cell antigen receptor (TCR)-dependent cytolytic and cytokine responses by CMV-specific CD28- CD8alphabeta T cells. This function overcame viral interference with MHC class I antigen presentation. Combined triggering of TCR-CD3 complexes and NKG2D induced interleukin 2 production and T cell proliferation. Thus NKG2D functioned as a costimulatory receptor that can substitute for CD28.
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PMID:Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. 1122 16

The human cytomegalovirus glycoprotein, UL16, binds to two members of a novel family of molecules, the ULBPs, and to the MHC class I homolog, MICB. The ULBPs are GPI-linked glycoproteins belonging to the extended MHC class I family but are only distantly related to MICB. The ULBP and MICB molecules are ligands for the activating receptor, NKG2D/DAP10, and this interaction is blocked by a soluble form of UL16. The ULBPs stimulate cytokine and chemokine production from NK cells, and expression of ULBPs in NK cell-resistant target cells confers susceptibility to NK cell cytotoxicity. Masking of NK cell recognition of ULBP or MIC antigens by UL16 provides a potential mechanism by which human cytomegalovirus-infected cells might evade attack by the immune system.
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PMID:ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor. 1123 45

The human MHC class I chain-related genes (MICA and MICB) are located within the HLA class I region of chromosome 6. Their organization, expression and products differ considerably from classical HLA class I genes. MIC proteins are considered to be markers of "stress" in the epithelia, and act as ligands for cells expressing a common activatory natural killer-cell receptor (NKG2D). Molecular models are now available for the MICA protein, both bound and complexed with NKG2D. MICA molecules appear to be highly flexible and polymorphic, although the functional relevance and implications of their polymorphism have yet to be fully discerned.
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PMID:MICA and MICB genes: can the enigma of their polymorphism be resolved? 1142 22

Several inhibitory and activating receptors involved in natural killer cell activation have been characterized. The increasing knowledge about their ligands, including classical MHC class I molecules, non-classical MHC class I molecules and MHC class I-related molecules, is shedding new light on the targets of innate immune recognition. While classical MHC class I molecules are constitutively expressed, some MHC class I-related (MIC) molecules, however, are stress-induced by ill-defined stimuli. Two families of ligands for the human activating NKG2D receptor have been identified. These are the MIC proteins encoded by two highly polymorphic genes within the MHC class I and the retinoic acid-inducible early gene-1-like (also designated UL16-binding) proteins encoded by genes outside the MHC. For the mouse NKG2D receptor, one family, containing at least five distinct ligands, has been described. A better understanding about how targets signal their distress, which renders them susceptible to natural killer (NK)-cell attack, will help to define the role of NK cells in antimicrobial and antitumor immunity and transplantation.
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PMID:Ligands for natural killer cell receptors: redundancy or specificity. 1151 37

Cellular immune responses to melanoma are tightly regulated and include specific T cell responses to self antigens such as Mart-1 and gp100. Thus, additional signals apart from those mediated by the T cell receptor are needed to ensure T cell activation. Recently, the stress inducible major histocompatibility complex molecules, MHC class I related chain, were identified as an activator of both natural killer and T cells via interaction with their receptor NKG2D. Herein, we report the expression of MIC in 31 of 40 primary cutaneous melanomas and in 13 of 20 metastatic lesions. Moreover, lymphocytes infiltrating the tumor were found to express NKG2D. Detailed analysis identified both CD3+ T cells as well as CD56+ natural killer cells contributing to this NKG2D+ tumor infiltrating lymphocyte population present.
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PMID:Expression of stress-induced MHC class I related chain molecules on human melanoma. 1191 5

Natural killer (NK) cells function through a diverse array of cell-surface natural killer receptors (NCRs). NCRs specific for classical and non-classical MHC class I proteins, expressed in complex patterns of inhibitory and activating isoforms on overlapping, but distinct, subsets of NK cells, play an important role in immunosurveillance against cells that have reduced MHC class I expression as a result of infection or transformation. Another NCR, NKG2D, is an activating NCR first identified on NK cells, but subsequently found on macrophages and a variety of T cell types. NKG2D ligands in rodents include the MHC class I-like proteins RAE-1 and H60 and, in humans, ULBPs and the cell stress-inducible proteins MICA and MICB. NKG2D-MIC and -RAE-1 recognition events have been implicated in anti-viral and -tumor immune responses. Crystallographic analyses of NKG2D-MICA and -RAE-1 complexes reveal an unusual mode of recognition that apparently tolerates a surprising degree of ligand plasticity while generating affinities that are among the strongest TCR- or NCR-ligand affinities, thus, far described.
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PMID:Asymmetric ligand recognition by the activating natural killer cell receptor NKG2D, a symmetric homodimer. 1195 95

Human gamma delta T cells with the TCR variable region V(delta)1 occur mainly in epithelia and respond to stress-induced expression of the MHC class I-related chains A and B, which have no function in Ag presentation. MIC function as ligands for NKG2D-DAP10, an activating receptor complex that triggers NK cells, costimulates CD8 alpha beta and V(gamma)9V(delta)2 gamma delta T cells, and is required for stimulation of V(delta)1 gamma delta T cells. It is unresolved, however, whether triggering of V(delta)1 gamma delta TCRs is also mediated by MIC or by unidentified cell surface components. Soluble MICA tetramers were used as a binding reagent to demonstrate specific interactions with various V(delta)1 gamma delta TCRs expressed on transfectants of a T cell line selected for lack of NKG2D. Tetramer binding was restricted to TCRs derived from responder T cell clones classified as reactive against a broad range of MIC-expressing target cells and was abrogated when TCRs were composed of mismatched gamma- and delta-chains. These results and the inability of V(delta)1 gamma delta T cells to respond to target cells expressing the ULBP/N2DL ligands of NKG2D, which are highly divergent from MIC, indicate that MIC delivers both the TCR-dependent signal 1 and the NKG2D-dependent costimulatory signal 2. This dual function may serve to prevent erroneous gamma delta T cell activation by cross-reactive cell surface determinants.
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PMID:T cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial gamma delta T cells. 1213 44

MIC-A and MIC-B are distant MHC class I homologs that serve as stress-inducible Ags on epithelial and epithelially derived cells. They are ligands for the widely expressed activating immunoreceptor NKG2D. To define the structural and functional consequences of sequence differences between MIC-A and MIC-B and between alleles of MIC-A and alleles of MIC-B, we determined the crystal structure of one allele of human MIC-B. Comparisons between the two previously reported MIC-A crystal structures and the MIC-B crystal structure show that, as expected, MIC-B is very similar in structure to MIC-A and likely interacts with NKG2D in an analogous manner. The interdomain flexibility observed in the MIC-A structures, a feature unique to MIC proteins among MHC class I proteins and homologs, is also displayed by MIC-B, with an interdomain relationship intermediate between the two examples of MIC-A structures. Mapping sequence variations onto the structures of MIC-A and MIC-B reveals patterns completely distinct from those displayed by classical MHC class I proteins, with a number of substitutions falling on positions likely to affect interactions with NKG2D, but with other positions lying distant from the NKG2D binding sites or buried within the core of the proteins.
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PMID:Structural studies of allelic diversity of the MHC class I homolog MIC-B, a stress-inducible ligand for the activating immunoreceptor NKG2D. 1213 64

Major histocompatibility complex (MHC) class I chain-related genes, MICA and MICB, are located centromeric to human leukocyte antigen B (HLA-B) on chromosome 6. In response to stress stimuli, MIC is expressed on epithelial, endothelial and fibroblast cells, but not lymphocytes and has been demonstrated to ligate the natural killer (NK) cell receptor, NKG2D. Nucleotide sequences of MICA and MICB are highly polymorphic and several methods have been established to identify these polymorphisms, including sequence-based typing and sequence-specific oligonucleotide probing. In this study we have developed a high-resolution polymerase chain reaction-sequence-specific primer (PCR-SSP) phototyping scheme that detects all WHO-recognized MICA alleles and all 12 MICB alleles. Our method will also recognize a MICA deletion haplotype and distinguish between MICA alleles with different binding affinities for NKG2D, encoded by a non-synonymous nucleotide substitution in codon 129. Furthermore, our scheme targets almost 90% of the dimorphic codon positions in exons 2, 3, and 4, which result in non-synonymous amino acid changes. This method can be used to determine MIC allele frequencies within different populations, as well as investigate MIC associations in cohorts of patients with autoimmune and infectious diseases and explore the impact of MIC on the survival of solid organ and stem cell transplants.
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PMID:High resolution molecular phototyping of MICA and MICB alleles using sequence specific primers. 1217 34

Murine NKG2D is known to recognize H60 and five RAE1 variants. The human homologue recognizes both inducible MHC class I chain-related gene and constitutive (UL16-binding protein (ULBP)) ligands. Widely expressed, the latter are thought to mark transformed or infected cells for destruction by NK cells in the context of down-regulated cell surface class I (i.e., the "missing self"-response). Unlike MIC and ULBP however, mRNA for the murine ligands appears only in very limited contexts in the mature animal. In this study, we describe a NKG2D ligand termed "murine ULBP-like transcript 1 (MULT1) whose mRNA appears to be widely expressed in adult parenchyma. This molecule possesses MHC class I-like alpha1 and alpha2 domains as well as a large cytoplasmic domain. Recombinant MULT1 binds NKG2D with relatively high affinity (K(D) approximately 6 nM) and low k(off) (approximately 0.006s(-1)). Expression of MULT1 by normally resistant RMA cells results in their susceptibility to lysis by C57BL/6 splenocytes.
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PMID:Cutting edge: murine UL16-binding protein-like transcript 1: a newly described transcript encoding a high-affinity ligand for murine NKG2D. 1237 Mar 32


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