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

EMBO Molecular Medicine

Antje Isernhagen¹  Dörthe Malzahn⁵  Elena Viktorova⁵  Leslie Elsner¹  Sebastian Monecke¹  Frederike von Bonin³  Markus Kilisch⁴  Janne Marieke Wermuth³  Neele Walther³  Yesilda Balavarca⁵  Christiane Stahl-Hennig²  Michael Engelke¹  Lutz Walter⁶  Heike Bickeböller⁵  Dieter Kube³  Gerald Wulf³ 

[1] Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany;Unit of Infection Models, German Primate Center, Göttingen, Germany;Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany;Institute of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany;Institute of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, Germany;Primate Genetics Laboratory, German Primate Center, Göttingen, Germany

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

DOI  :  10.15252/emmm.201505246

来源: Wiley

【 摘 要 】

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.

Synopsis

Allogeneic hematopoietic stem cell transplantation still has a high risk of post-transplant complications including graft versus host disease and relapse of malignancy. Detection of single nucleotide polymorphisms may help to provide a risk-adapted treatment.

• The MICA-129Met/Val dimorphism was associated with an increased survival and a reduced risk to die due to acute graft versus host disease in a cohort of 452 patients.
• The survival of MICA-129Val/Val genotype carriers was improved when treated with antithymocyte globulin (ATG).
• The MICA-129Met isoform triggered more NK-cell cytotoxicity and interferon-γ release and it co-stimulated cytotoxic T cells faster.
• The MICA-129Met isoform also induced a faster and stronger down-regulation of NKG2D on NK and cytotoxic T cells limiting the initially stronger functional effects.
• MICA-129Val/Val carriers might profit from a T-cell depleting treatment since this MICA variant has a lower ability to down-regulate NKG2D and to limit the activation of alloreactive T cells.

【 授权许可】

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© 2015 The Authors. Published under the terms of the CC BY 4.0 license

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