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*, David J. Roberts

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

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-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 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 α-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-γ-producing) profile and are suitable for testing selective immunotherapies that might be applicable in vivo.

Original languageEnglish
Pages (from-to)677-686
Number of pages10
JournalJournal of Immunology
Volume183
Issue number1
DOIs
Publication statusPublished - 1 Jul 2009
Externally publishedYes

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