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

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

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) undergoi...

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Main Authors: Antje Isernhagen, Dörthe Malzahn, Elena Viktorova, Leslie Elsner, Sebastian Monecke, Frederike von Bonin, Markus Kilisch, Janne Marieke Wermuth, Neele Walther, Yesilda Balavarca, Christiane Stahl‐Hennig, Michael Engelke, Lutz Walter, Heike Bickeböller, Dieter Kube, Gerald Wulf, Ralf Dressel
Format: Article
Language:English
Published: Springer Nature 2015-10-01
Series:EMBO Molecular Medicine
Subjects:
cytotoxic T cells
graft‐versus‐host disease
NK‐cell receptors
NK cells
single nucleotide polymorphism
Online Access:https://doi.org/10.15252/emmm.201505246
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Summary: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.
ISSN:1757-4676
1757-4684

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