title: T cell responses to human platelet antigen-1a involve a unique form of indirect allorecognition.
abstract: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a pregnancy-related condition caused by maternal antibodies binding an alloantigen on fetal platelets. In most cases the alloantigen is formed by a single amino acid, integrin β3 Leu33, referred to as human platelet antigen-1a (HPA-1a). Production of anti-HPA-1a antibodies likely depends on CD4+T cells that recognize the same alloantigen in complex with the HLA-DRA/DRB3*01:01 molecule. While this complex is well characterized, T cell recognition of it is not. Here, to examine the nature of antigen recognition by HPA-1a-specific T cells, we assayed native and synthetic variants of the integrin β3 peptide antigen for binding to DRA/DRB3*01:01-positive antigen-presenting cells and for T cell activation. We found that HPA-1a-specific T cells recognize non-allogeneic integrin β3 residues anchored to DRA/DRB3*01:01 by the allogeneic Leu33, which itself is not directly recognized by these T cells. Furthermore, these T cell responses are diverse, with different T cells depending on different residues for recognition. This represents a unique form of indirect allorecognition in which a non-allogeneic peptide sequence becomes immunogenic by stable anchoring to MHC by an allogeneic residue.
authors.affiliation: Division of Diagnostic Services, Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway.|Immunology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Maria Therese
authors.initials: MT
authors.lastname: Ahlen
authors.affiliation: Immunology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Anne
authors.initials: A
authors.lastname: Husebekk
authors.affiliation: Immunology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Ida Løken
authors.initials: IL
authors.lastname: Killie
authors.affiliation: Division of Diagnostic Services, Department of Laboratory Medicine, University Hospital of North Norway, Tromsø, Norway.|Immunology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Bjørn
authors.initials: B
authors.lastname: Skogen
authors.affiliation: Immunology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.
authors.forename: Tor Brynjar
authors.initials: TB
authors.lastname: Stuge
mesh_terms: D000328:Adult; D016824:Antigens, Human Platelet / Q000276:immunology*; D001792:Blood Platelets; D005260:Female; D059826:HLA-DRB3 Chains; D006801:Humans; D039661:Integrin beta3 / Q000276:immunology*; D011247:Pregnancy; D013601:T-Lymphocytes / Q000276:immunology*; D054098:Thrombocytopenia, Neonatal Alloimmune / Q000276:immunology*
chemical_list: D016824:Antigens, Human Platelet; D059826:HLA-DRB3 Chains; D039661:Integrin beta3