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EMBO Mol Med. 2015 Nov;7(11):1480-502. doi: 10.15252/emmm.201505246.

The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation.

Author information

1
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
2
Institute of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, Germany.
3
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
4
Institute of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany.
5
Unit of Infection Models, German Primate Center, Göttingen, Germany.
6
Primate Genetics Laboratory, German Primate Center, Göttingen, Germany.
7
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany rdresse@gwdg.de.

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.

KEYWORDS:

NK cells; NK‐cell receptors; cytotoxic T cells; graft‐versus‐host disease; single nucleotide polymorphism

PMID:
26483398
PMCID:
PMC4644379
DOI:
10.15252/emmm.201505246
[Indexed for MEDLINE]
Free PMC Article

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