Functional effects of the MICA-129 dimorphism on NK cell activity and association with the outcome of hematopoietic stem cell transplantation
von Antje Isernhagen
Datum der mündl. Prüfung:2014-04-01
Betreuer:Prof. Dr. Lutz Walter
Gutachter:Prof. Dr. Heidi Hahn
Gutachter:Prof. Dr. Ralf Dressel
EnglischThe MHC class I chain-related molecule A (MICA) is a highly polymorphic ligand for the activating natural killer (NK) cell receptor NKG2D (NK group 2, member D). The single nucleotide polymorphism (SNP) at position 454 (A → G, rs1051792) leads to an amino acid substitution of methionine by valine (Met → Val) at position 129 in the α2 domain of the MICA protein. In this study, we evaluated how the MICA-129Met/Val polymorphism affects NK cell function and whether it is associated with the outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Results of the functional analyses using transfected cell lines and recombinant proteins for both variants revealed differences between both MICA-129 variants. The MICA-129Met isoform was characterized by higher NKG2D binding avidity (P = 0.0016), faster and stronger NKG2D signaling, triggering of more NK cell cytotoxicity (granule exocytosis, P = 0.0174; target cell lysis, P = 0.0044) and interferon-gamma (IFN-y) release (P < 0.0001) but also increased NKG2D down-regulation (P ≤ 0.0006). Especially at low MICA expression intensity, the Met variant had stronger functional effects than the Val variant. However, the degree of NK cell cytotoxicity and cytokine production increased steadily with expression intensity of the MICA-129Val variant, whereas an enhanced expression of the MICA-129Met isoform had no or even a negative effect on NK cell function. These data demonstrate a strong interdependency of the MICA expression intensity and the MICA-129 genotype. To elucidate whether the differences between the MICA variants are indeed clinically relevant, the MICA-129 dimorphism was determined in a cohort of patients undergoing allogeneic HSCT in the Department of Hematology and Medical Oncology at the University Medical Center Göttingen (320 genotyped patient/donor (P/D) pairs with clinical characteristics). In recipients matched on the MICA-129 genotype, MICA-129Met variants increased the chance of survival (P = 0.0395) and reduced the risk to die due to acute graft-versus-host disease (aGVHD, P = 0.0117), although homozygous carriers had an increased risk to experience this complication (P = 0.0361) after HSCT. Thus, the presence of the high avidity variant of MICA may lead to a favorable outcome of HSCT due to initially stronger NKG2D signaling followed, however, by a more rapid NKG2D counter-regulation. Taken together, these data indicate that the MICA-129Met/Val polymorphism is functionally relevant and fine-tunes NK cell activity suggesting that it has direct effects on the outcome of HSCT but the intensity of MICA expression is a major confounding factor.
Keywords: MICA-129; NKG2D; HSCT; GVHD