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Immunogenetics. 2016 Feb;68(2):109-23. doi: 10.1007/s00251-015-0884-8. Epub 2015 Nov 19.

The MICA-129Met/Val dimorphism affects plasma membrane expression and shedding of the NKG2D ligand MICA.

Author information

1
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Humboldtallee 34, 37073, Göttingen, Germany.
2
Department of Radiation Oncology, Klinikum rechts der Isar, Technische Universität München (TUM), Munich, Germany.
3
Institute of Innovative Radiotherapy (iRT), Radiation Immune Biology, Department of Radiation Sciences (DRS), Helmholtz Zentrum München, Munich, Germany.
4
DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Göttingen, Germany.
5
Primate Genetics Laboratory, German Primate Center, Göttingen, Germany.
6
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Humboldtallee 34, 37073, Göttingen, Germany. rdresse@gwdg.de.
7
DZHK (German Center for Cardiovascular Research), Partner site Göttingen, Göttingen, Germany. rdresse@gwdg.de.

Abstract

The MHC class I chain-related molecule A (MICA) is a ligand for the activating natural killer (NK) cell receptor NKG2D. A polymorphism causing a valine to methionine exchange at position 129 affects binding to NKG2D, cytotoxicity, interferon-γ release by NK cells and activation of CD8(+) T cells. It is known that tumors can escape NKG2D-mediated immune surveillance by proteolytic shedding of MICA. Therefore, we investigated whether this polymorphism affects plasma membrane expression (pmMICA) and shedding of MICA. Expression of pmMICA was higher in a panel of tumor (n = 16, P = 0.0699) and melanoma cell lines (n = 13, P = 0.0429) carrying the MICA-129Val/Val genotype. MICA-129Val homozygous melanoma cell lines released more soluble MICA (sMICA) by shedding (P = 0.0015). MICA-129Met or MICA-129Val isoforms differing only in this amino acid were expressed in the MICA-negative melanoma cell line Malme, and clones with similar pmMICA expression intensity were selected. The MICA-129Met clones released more sMICA (P = 0.0006), and a higher proportion of the MICA-129Met than the MICA-129Val variant was retained in intracellular compartments (P = 0.0199). The MICA-129Met clones also expressed more MICA messenger RNA (P = 0.0047). The latter phenotype was also observed in mouse L cells transfected with the MICA expression constructs (P = 0.0212). In conclusion, the MICA-129Met/Val dimorphism affects the expression density of MICA on the plasma membrane. More of the MICA-129Met variants were retained intracellularly. If expressed at the cell surface, the MICA-129Met isoform was more susceptible to shedding. Both processes appear to limit the cell surface expression of MICA-129Met variants that have a high binding avidity to NKG2D.

KEYWORDS:

Major histocompatibility complex (MHC) class I chain-related molecules A (MICA); Plasma membrane expression; Proteolytic shedding; Single nucleotide polymorphism; Tumor cells

PMID:
26585323
PMCID:
PMC4728179
DOI:
10.1007/s00251-015-0884-8
[Indexed for MEDLINE]
Free PMC Article

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