The MICA-129 dimorphism affects NKG2D signaling and outcome of hematopoietic stem cell transplantation.
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.
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
Antje
A
Isernhagen
Institute of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, Germany.
Dörthe
D
Malzahn
Institute of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, Germany.
Elena
E
Viktorova
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
Leslie
L
Elsner
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
Sebastian
S
Monecke
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
Frederike
F
von Bonin
Institute of Molecular Biology, University Medical Center Göttingen, Göttingen, Germany.
Markus
M
Kilisch
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
Janne Marieke
JM
Wermuth
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
Neele
N
Walther
Institute of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, Germany.
Yesilda
Y
Balavarca
Unit of Infection Models, German Primate Center, Göttingen, Germany.
Christiane
C
Stahl-Hennig
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
Michael
M
Engelke
Primate Genetics Laboratory, German Primate Center, Göttingen, Germany.
Lutz
L
Walter
Institute of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, Germany.
Heike
H
Bickeböller
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
Dieter
D
Kube
Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
Gerald
G
Wulf
Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany rdresse@gwdg.de.
Ralf
R
Dressel
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic; D005260:Female; D006086:Graft vs Host Disease / Q000401:mortality* / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics*; D020125:Mutation, Missense; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
D015395:Histocompatibility Antigens Class I; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D050505:Mutant Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D007371:Interferon-gamma
NK cells; NK‐cell receptors; cytotoxic T cells; graft‐versus‐host disease; single nucleotide polymorphism