Impact of the MICA-129Met/Val Dimorphism on NKG2D-Mediated Biological Functions and Disease Risks

Abstract

The major histocompatibility complex (MHC) class I chain-related A (MICA) is the most polymorphic non-classical MHC class I gene in humans. It encodes a ligand for NKG2D (NK group 2, member D), an activating natural killer (NK) receptor that is expressed mainly on NK cells and CD8+ T cells. The single-nucleotide polymorphism (SNP) rs1051792 causing a valine (Val) to methionine (Met) exchange at position 129 of the MICA protein is of specific interest. It separates MICA into isoforms that bind NKG2D with high (Met) and low affinities (Val). Therefore, this SNP has been investigated for associations with infections, autoimmune diseases, and cancer. Here, we systematically review these studies and analyze them in view of new data on the functional consequences of this polymorphism. It has been shown recently that the MICA-129Met variant elicits a stronger NKG2D signaling, resulting in more degranulation and IFN-γ production in NK cells and in a faster costimulation of CD8+ T cells than the MICA-129Val variant. However, the MICA-129Met isoform also downregulates NKG2D more efficiently than the MICA-129Val isoform. This downregulation impairs NKG2D-mediated functions at high expression intensities of the MICA-Met variant. These features of the MICA-129Met/Val dimorphism need to be considered when interpreting disease association studies. Particularly, in the field of hematopoietic stem cell transplantation, they help to explain the associations of the SNP with outcome including graft-versus-host disease and relapse of malignancy. Implications for future disease association studies of the MICA-129Met/Val dimorphism are discussed.

High-Throughput MICA/B Genotyping of Over Two Million Samples: Workflow and Allele Frequencies

“…Especially the MICA-129Met/Val dimorphism encoded by the SNP rs1051792 has received attention because it separates the different MICA alleles into NKG2D-receptor low (Val)-and high (Met)affinity binding alleles (21). Health risk associations have been shown for several autoimmune diseases, cancer and viral infections (22)(23)(24)(25)(26)(27). Furthermore, matching of MICA, including the MICA-129 dimorphism, between donor and patient has been correlated with improved outcome of unrelated hematopoietic stem cell transplantation and reduced acute and chronic graftvs.-host disease (28)(29)(30)(31)(32).…”

Budowa i funkcja ludzkich antygenów zgodności tkankowej. Część 3. Rola antygenów MHC w chorobach reumatycznych

“…W części przypadków zidentyfikowano powiązania funkcji antygenów zgodności tkankowej z SNP. Polimorfizm pojedynczego nukleotydu rs1051792, co powoduje wymianę waliny na metioninę w pozycji 129 łańcucha MICA zwiększa powinowactwo antygenu do receptora NKG2D komórek NK (natural killer), co skutkuje silniejszą stymulacją tych komórek, większą degranulacją i wytwarzaniem IFN-g [74]. Analogiczny mechanizm może tłumaczyć powiązania pomiędzy występowaniem RZS a ekspresją MICA-250 (rs1051794, wymiana lizyny na kwas glutaminowy w pozycji 196) (rzs11).…”

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

“…An SNP within this gene, rs1051792, which leads to an amino acid exchange from valine to methionine at position 129 (56), was investigated for its association with the outcome of HSCT. We found that the MICA-129Met variant was associated with an increased overall survival and a reduced risk to die from aGvHD, despite homozygous carriers of the MICA-129Val allele having an increased risk of developing aGvHD (57).…”