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

R Rayment, TW Kooij, W Zhang, C Siebold… - The Journal of …, 2009 - journals.aai.org
R Rayment, TW Kooij, W Zhang, C Siebold, MF Murphy, D Allen, N Willcox, DJ Roberts
The Journal of Immunology, 2009journals.aai.org
Maternal alloantibodies against the human platelet Ag (HPA)-1a allotype of the platelet β 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 …
Abstract
Maternal alloantibodies against the human platelet Ag (HPA)-1a allotype of the platelet β 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 α-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-γ-producing) profile and are suitable for testing selective immunotherapies that might be applicable in vivo.
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