Steinle, A. et al. Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics 53, 279-287

Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, United States
Immunogenetics (Impact Factor: 2.23). 04/2001; 53(4):279-287. DOI: 10.1007/s002510100325
Source: PubMed


NKG2D is an activating receptor that is expressed on most natural killer (NK) cells, CD8 &#33# T cells, and &#37' T cells. Among its ligands is the distant major histocompatibility complex class I homolog MICA, which has no function in antigen presentation but is induced by cellular stress. To extend previous functional evidence, the NKG2D-MICA interaction was studied in isolation. NKG2D homodimers formed stable complexes with monomeric MICA in solution, demonstrating that no other components were required to facilitate this interaction. MICA glycosylation was not essential but enhanced complex formation. Soluble NKG2D also bound to cell surface MICB, which has structural and functional properties similar to those of MICA. Moreover, NKG2D stably interacted with surface molecules encoded by three newly identified cDNA sequences (N2DL-1, -2, and -3), which are identical to the human ULBP proteins and may represent homologs of the mouse retinoic acid-early inducible family of NKG2D ligands. Because of the substantial sequence divergence among these molecules, these results indicated promiscuous modes of receptor binding. Comparison of allelic variants of MICA revealed large differences in NKG2D binding that were associated with a single amino acid substitution at position 129 in the Ō domain. Varying affinities of MICA alleles for NKG2D may affect thresholds of NK-cell triggering and T-cell modulation.

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Available from: Roland K Strong, Sep 01, 2015
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    • "A broad range of MICA expression intensities was observed on different clones, but on average, these intensities were similar for both variants (Appendix Fig S1B). Analysis of the ratio of MICA expression and NKG2D binding revealed clearly a higher avidity of the MICA- 129Met than MICA-129Val variant for NKG2D (Appendix Fig S1C and D) in accord with previous results (Steinle et al, 2001). Notably, binding of NKG2D to the MICA-129Met isoform was more dependent on the intensity of MICA expression on individual clones (coefficient of determination R 2 = 0.62) than to the MICA-129Val isoform (R 2 = 0.39). "
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    ABSTRACT: The MHC class I chain-related molecule A (MICA) is a highly polymorphic ligand for the activating natural killer (NK)-cell receptor NKG2D. A single nucleotide polymorphism causes a valine to methionine exchange at position 129. Presence of a MICA-129Met allele in patients (n = 452) undergoing hematopoietic stem cell transplantation (HSCT) increased the chance of overall survival (hazard ratio [HR] = 0.77, P = 0.0445) and reduced the risk to die due to acute graft-versus-host disease (aGVHD) (odds ratio [OR] = 0.57, P = 0.0400) although homozygous carriers had an increased risk to experience this complication (OR = 1.92, P = 0.0371). Overall survival of MICA-129Val/Val genotype carriers was improved when treated with anti-thymocyte globulin (HR = 0.54, P = 0.0166). Functionally, the MICA-129Met isoform was characterized by stronger NKG2D signaling, triggering more NK-cell cytotoxicity and interferon-γ release, and faster co-stimulation of CD8(+) T cells. The MICA-129Met variant also induced a faster and stronger down-regulation of NKG2D on NK and CD8(+) T cells than the MICA-129Val isoform. The reduced cell surface expression of NKG2D in response to engagement by MICA-129Met variants appeared to reduce the severity of aGVHD.
    EMBO Molecular Medicine 10/2015; 7(11). DOI:10.15252/emmm.201505246 · 8.67 Impact Factor
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    • "It displays a high degree of allelic polymorphism in exon 5, encoding the transmembrane region [21], and in exons 2, 3, and 4, encoding the three extracellular domains alfa- 1, alfa-2, and alfa-3 of the MICA protein, respectively [22]. Although the functional significance of MICA gene diversity is unknown, certain changes in the amino acid sequence of MICA proteins could influence the affinity with its cognate NKG2D receptor [23]. Thus, it has been demonstrated that the presence of methionine (Met) or valine (Val) at codon 129 of the alfa-2 domain may confer strong or weak affinity, respectively. "
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    ABSTRACT: A limited number of studies have been performed so far on the polymorphism in the transmembrane region (exon 5) of the major histocompatibility complex class I chain-related gene A (MICA) in patients with melanoma. However, the influence of MICA polymorphism in extracellular domains (exons 2, 3, and 4) has not been investigated on melanoma disease. This study aims to characterize the influence of extracellular MICA polymorphism, and its previously described linkage disequilibrium with HLA-B locus, on patients with cutaneous melanoma from southeastern Spain. For this purpose, MICA and HLA-B genotyping was performed in 233 patients and 200 ethnically matched controls by luminex technology. Patients were classified according to the presence of methionine or valine at codon 129 of MICA gene. We found a high frequency of MICA*009 in melanoma patients compared with controls (, Pc = 0.03). Our results also showed an association between MICA*009 and HLA-B*51 alleles in both patients and controls. This association was stronger in patients than controls (). However, a multivariate logistic regression model showed that neither MICA*009 nor the combination MICA*009/HLA-B*51 was associated with melanoma susceptibility. No relationship was observed between MICA-129 dimorphism and melanoma nor when MICA polymorphism was evaluated according to clinical findings at diagnosis.
    Disease markers 04/2015; 2015:1-6. DOI:10.1155/2015/831864 · 1.56 Impact Factor
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    • "NKG2D interacts with various ligands: human MICA/B (MHC class I chain-related protein A and B) and ULBP1–6 (UL16-binding proteins 1–6) or mouse Rae1 (retinoic acid early transcript 1), H60 (histocompatibility 60) and Mult1 (mouse UL16-binding protein-like transcript 1) [8,15,16]. The ligands are upregulated by cellular stress including viral infection, inflammation, and transformation, indicating a physiologic role in immune responses to various cellular hazards [17,18]. "
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    ABSTRACT: Migration of encephalitogenic CD4(+) T lymphocytes across the blood-brain barrier is an essential step in the pathogenesis of multiple sclerosis (MS). We here demonstrate that expression of the co-stimulatory receptor NKG2D defines a subpopulation of CD4(+) T cells with elevated levels of markers for migration, activation, and cytolytic capacity especially when derived from MS patients. Furthermore, CD4(+)NKG2D(+) cells produce high levels of proinflammatory IFN-γ and IL-17 upon stimulation. NKG2D promotes the capacity of CD4(+)NKG2D(+) cells to migrate across endothelial cells in an in vitro model of the blood-brain barrier. CD4(+)NKG2D(+) T cells are enriched in the cerebrospinal fluid of MS patients, and a significant number of CD4(+) T cells in MS lesions coexpress NKG2D. We further elucidated the role of CD4(+)NKG2D(+) T cells in the mouse system. NKG2D blockade restricted central nervous system migration of T lymphocytes in vivo, leading to a significant decrease in the clinical and pathologic severity of experimental autoimmune encephalomyelitis, an animal model of MS. Blockade of NKG2D reduced killing of cultivated mouse oligodendrocytes by activated CD4(+) T cells. Taken together, we identify CD4(+)NKG2D(+) cells as a subpopulation of T helper cells with enhanced migratory, encephalitogenic and cytotoxic properties involved in inflammatory CNS lesion development.
    PLoS ONE 12/2013; 8(11):e81455. DOI:10.1371/journal.pone.0081455 · 3.23 Impact Factor
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