A unique major histocompatibility complex Class II–binding register correlates with HLA-DR11–associated immunogenicity of the major K blood group antigen

Devi Gunasekera, James C. Zimring, Kathleen P. Pratt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Kell is a glycoprotein expressed on red blood cells (RBCs). Its K and k variants contain either Met (K antigen) or Thr (k antigen) at Position 193, respectively. Development of anti-K after K-mismatched antigen exposure via blood transfusions or pregnancy can destroy RBCs, leading to hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. The immunogenicity of overlapping 15-mer Kell peptides with M193 or T193 at every possible position was investigated previously. Interestingly, Peptide W179 to M193, with the polymorphic M193T residue at the peptide's C-terminus, was the most effective at stimulating CD4 T cells from a series of K-immunized women. STUDY DESIGN AND METHODS: This study investigates the basis for HLA restriction of anti-K immune responses. Major histocompatibility complex Class II (MHCII)-binding prediction algorithms and quantitative peptide–MHCII-binding assays were employed to determine the binding registers; anchor residues; and affinities of wild-type, truncated, and sequence-modified K and k peptides. Predictions were generated using Immune Epitope Database and ProPred algorithms. Competitive peptide–MHCII-binding assays utilized 12 recombinant HLA-DR proteins, K and k peptides, and high-affinity MHCII-restricted reference peptides. RESULTS: The peptide–MHCII-binding assays identified a unique K peptide–binding register (W179-S187) restricted to HLA-DRB1*11:01, in addition to partially overlapping binding registers that included the K/k M193T polymorphic site and that bound promiscuously to multiple HLA-DR proteins. CONCLUSION: Three partially overlapping MHCII-binding motifs for HLA-DRB1*11:01 result in high-avidity K-peptide binding, which may contribute to HLA-DR11-restricted immunogenicity associated with the K allele.

Original languageEnglish
Pages (from-to)1171-1181
Number of pages11
JournalTransfusion
Volume58
Issue number5
DOIs
StatePublished - May 2018
Externally publishedYes

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