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* 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 β3 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Muscular Dystrophy Campaign, Myasthenia Gravis Association, and National Health Service Blood and Transplant and benefited from funding by the United Kingdom National Health Service R&D Directorate, the National Institute for Health Research Centre Programme, and the Howard Hughes Medical Institute.
R.R., D.J.R., M.M., and D.A. conceived and planned the study; N.W. also helped to design it, and provided clone KB-D1; R.R. performed the T cell experiments; W.Z. helped in the ELISPOT assays and T cell cloning. C.S. did the molecular modeling; T.K. did the TCR identification. R.R. and N.W. prepared the first draft of the paper, and all authors helped to finalize it.
2 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
3 Abbreviations used in this paper: FMAIT, fetomaternal/neonatal alloimmune thrombocytopenia; AChR, acetylcholine receptor; DC, dendritic cell; HPA, human platelet Ag; IvIg, intravenous immunoglobulin; MG, myasthenia gravis; PBMCx, irradiated peripheral blood mononuclear cell; rh, recombinant human; RH5, RPMI with 5% heat-inactivated human HPA-1b plasma.
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