title: Inflammation-associated nitrotyrosination affects TCR recognition through reduced stability and alteration of the molecular surface of the MHC complex.
abstract: Nitrotyrosination of proteins, a hallmark of inflammation, may result in the production of MHC-restricted neoantigens that can be recognized by T cells and bypass the constraints of immunological self-tolerance. Here we biochemically and structurally assessed how nitrotyrosination of the lymphocytic choriomeningitis virus (LCMV)-associated immunodominant MHC class I-restricted epitopes gp33 and gp34 alters T cell recognition in the context of both H-2D(b) and H-2K(b). Comparative analysis of the crystal structures of H-2K(b)/gp34 and H-2K(b)/NY-gp34 demonstrated that nitrotyrosination of p3Y in gp34 abrogates a hydrogen bond interaction formed with the H-2K(b) residue E152. As a consequence the conformation of the TCR-interacting E152 was profoundly altered in H-2K(b)/NY-gp34 when compared to H-2K(b)/gp34, thereby modifying the surface of the nitrotyrosinated MHC complex. Furthermore, nitrotyrosination of gp34 resulted in structural over-packing, straining the overall conformation and considerably reducing the stability of the H-2K(b)/NY-gp34 MHC complex when compared to H-2K(b)/gp34. Our structural analysis also indicates that nitrotyrosination of the main TCR-interacting residue p4Y in gp33 abrogates recognition of H-2D(b)/gp33-NY complexes by H-2D(b)/gp33-specific T cells through sterical hindrance. In conclusion, this study provides the first structural and biochemical evidence for how MHC class I-restricted nitrotyrosinated neoantigens may enable viral escape and break immune tolerance.
authors.affiliation: Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Chaithanya
authors.initials: C
authors.lastname: Madhurantakam
authors.forename: Adil D
authors.initials: AD
authors.lastname: Duru
authors.forename: Tatyana
authors.initials: T
authors.lastname: Sandalova
authors.forename: John R
authors.initials: JR
authors.lastname: Webb
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D018360:Crystallography, X-Ray; D006183:H-2 Antigens / Q000737:chemistry / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D055550:Protein Stability; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000276:immunology; D014764:Viral Proteins / Q000737:chemistry / Q000276:immunology
chemical_list: D000596:Amino Acids; D006183:H-2 Antigens; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014764:Viral Proteins; C002744:3-nitrotyrosine; D014443:Tyrosine