HLA-G mediated immune regulation is impaired by a single amino acid exchange in the alpha 2 domain

Hum Immunol. 2018 Jun;79(6):453-462. doi: 10.1016/j.humimm.2018.03.010. Epub 2018 Mar 29.

Abstract

The trade-off from HLA class I expression to HLA-G expression support the immune evasion of malignant cells. The essential role of the virtually invariant HLA-G in immune tolerance, tumor immunology and its expression frequency in immune privileged tissues is known; however the specific importance of allelic subtypes in immune responses is still not well understood. HLA-G01:01, 01:03 and 01:04 are the most prevalent allelic variants differing at residues 31 and 110, respectively. In cytotoxicity assays applying K562 cells transduced with the HLA-G variants as targets and NK cells as effectors the differential protective potential of HLA-G variants was analyzed. Their peptide profiles were determined utilizing soluble HLA technology. An increased protective potential of HLA-G01:04 could be observed. All variants exhibit a unique peptide repertoire with marginal overlap, while G01:04 differs in its peptide anchor profile substantially. The functional differences between HLA-G subtypes could be explained by the constraint of the bound peptides, modifying the pHLA-G accessible surface. For the first time a contribution of amino acid alterations within the HLA-G heavy chain for peptide selection and NK cell recognition could be observed. These results will be a step towards understanding immune tolerance and will guide towards personalized immune therapeutic strategies.

Keywords: HLA-G; NK cells; Peptides; Tolerance.

MeSH terms

  • Alleles
  • Amino Acids / genetics
  • Cytotoxicity, Immunologic
  • Genotype
  • HLA-G Antigens / genetics
  • HLA-G Antigens / metabolism*
  • Humans
  • Immune Tolerance
  • Immunomodulation
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation
  • Mutation / genetics
  • Peptides / genetics
  • Peptides / metabolism*
  • Polymorphism, Genetic
  • Protein Domains / genetics

Substances

  • Amino Acids
  • HLA-G Antigens
  • Peptides