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This Article Full Text (PDF) All Versions of this Article: jimmunol.0801473v1 183/1/677    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Rayment, R. Articles by Roberts, D. J. PubMed PubMed Citation Articles by Rayment, R. Articles by Roberts, D. J.

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

Rachel Rayment^*,, Taco W. Kooij^*, Wei Zhang^*,, Christian Siebold, Mike F. Murphy^*, Dave Allen^*, Nick Willcox^* and David J. Roberts^*

^*Nuffield Department of Clinical Laboratory Sciences and National Blood Service Oxford Centre, and Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom; Department of Haematology, Arthur Bloom Haemophilia Centre, University Hospital of Wales, Cardiff, United Kingdom; and Division of Structural Biology, University of Oxford, Oxford, United Kingdom

Maternal alloantibodies against the human platelet Ag (HPA)-1a allotype of the platelet |gb₃ 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 Pro³³ Leu substitution (HPA-1bHPA-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 Leu³³ (but not Pro³³ 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 -amino acids; indeed, a recently identified variant with Val³³ 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--producing) profile and are suitable for testing selective immunotherapies that might be applicable in vivo.

Address correspondence and reprint requests to Dr. David J. Roberts, Nuffield Department of Clinical Laboratory Sciences and National Blood Service Oxford Centre, John Radcliffe Hospital, Oxford OX3 9BQ, U.K. E-mail address: david.roberts{at}ndcls.ox.ac.uk or Dr. Nick Willcox, Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, U.K. E-mail address: nick.willcox{at}imm.ox.ac.uk.