title: Evidence for the specificity for platelet HPA-1a alloepitope and the presenting HLA-DR52a of diverse antigen-specific helper T cell clones from alloimmunized mothers.
abstract: Maternal alloantibodies against the human platelet Ag (HPA)-1a allotype of the platelet beta(3) integrin GpIIb/IIIa can cause severe fetal or neonatal hemorrhage. Almost all anti-HPA-1a-immune mothers are homozygous for HPA-1b and carry HLA-DR52a (DRB3*0101). The single Pro(33) -->Leu substitution (HPA-1b-->HPA-1a) was previously predicted to create a binding motif for HLA-DR52a that can lead to alloimmunization. We have isolated six CD4(+) T cell clones from three such mothers, which all respond to intact HPA-1a(+), but not HPA-1b(+), platelets. We used them to define the "core" and "anchor" residues of this natural T cell epitope. Molecular modeling based on a recently published crystal structure can explain the preferential presentation of the Leu(33) (but not Pro(33) variant) by HLA-DR52a rather than the linked HLA-DR3 or the allelic DR52b. The modeling also predicts efficient anchoring at position 33 by several alternative hydrophobic alpha-amino acids; indeed, a recently identified variant with Val(33) is presented well to two clones, and is therefore potentially alloimmunogenic. Finally, these HPA-1a-specific T cell clones use a variety of T cell receptors, but all have a "Th1" (IFN-gamma-producing) profile and are suitable for testing selective immunotherapies that might be applicable in vivo.
authors.affiliation: Nuffield Department of Clinical Laboratory Sciences and National Blood Service Oxford Centre, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Rayment
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kooij
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
authors.forename: Mike F
authors.initials: MF
authors.lastname: Murphy
authors.forename: Dave
authors.initials: D
authors.lastname: Allen
authors.forename: Nick
authors.initials: N
authors.lastname: Willcox
authors.forename: David J
authors.initials: DJ
authors.lastname: Roberts
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology*; D016824:Antigens, Human Platelet / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D039661:Integrin beta3; D007518:Isoantibodies / Q000096:biosynthesis / Q000097:blood*; D008969:Molecular Sequence Data; D009035:Mothers; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D016824:Antigens, Human Platelet; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; C061248:ITGB3 protein, human; D039661:Integrin beta3; D007518:Isoantibodies