title: A signal peptide derived from hsp60 binds HLA-E and interferes with CD94/NKG2A recognition.
abstract: Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical major histocompatibility complex (MHC) class I molecule which presents a restricted set of nonameric peptides, derived mainly from the signal sequence of other MHC class I molecules. It interacts with CD94/NKG2 receptors expressed on the surface of natural killer (NK) cells and T cell subsets. Here we demonstrate that HLA-E also presents a peptide derived from the leader sequence of human heat shock protein 60 (hsp60). This peptide gains access to HLA-E intracellularly, resulting in up-regulated HLA-E/hsp60 signal peptide cell-surface levels on stressed cells. Notably, HLA-E molecules in complex with the hsp60 signal peptide are no longer recognized by CD94/NKG2A inhibitory receptors. Thus, during cellular stress an increased proportion of HLA-E molecules may bind the nonprotective hsp60 signal peptide, leading to a reduced capacity to inhibit a major NK cell population. Such stress induced peptide interference would gradually uncouple CD94/NKG2A inhibitory recognition and provide a mechanism for NK cells to detect stressed cells in a peptide-dependent manner.
authors.affiliation: Microbiology and Tumor Biology Center, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Jakob
authors.initials: J
authors.lastname: Michaëlsson
authors.forename: Cristina
authors.initials: C
authors.lastname: Teixeira de Matos
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Klas
authors.initials: K
authors.lastname: Kärre
authors.forename: Kalle
authors.initials: K
authors.lastname: Söderström
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation; D015703:Antigens, CD / Q000502:physiology*; D018834:Chaperonin 60 / Q000737:chemistry / Q000378:metabolism*; D003602:Cytotoxicity, Immunologic; D006680:HLA Antigens / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type / Q000502:physiology*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D021382:Protein Sorting Signals / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell; D000097625:HLA-E Antigens
chemical_list: D015703:Antigens, CD; D018834:Chaperonin 60; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D037181:Lectins, C-Type; D055654:NK Cell Lectin-Like Receptor Subfamily C; D051920:NK Cell Lectin-Like Receptor Subfamily D; D021382:Protein Sorting Signals; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell; D000097625:HLA-E Antigens; C527054:KLRC1 protein, human; C497869:KLRD1 protein, human