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Monoclonal antibodies to HLA-E bind epitopes carried by unfolded beta sub(2)m-free heavy chains
Ist Teil von
European journal of immunology, 2015-08, Vol.45 (8), p.2356-2364
Erscheinungsjahr
2015
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
Since HLA-E heavy chains accumulate free of their light beta sub(2)-microglobulin ( beta sub(2)m) subunit, raising mAbs to folded HLA-E heterodimers has been difficult, and mAb characterization has been controversial. Herein, mAb W6/32 and 5 HLA-E-restricted mAbs (MEM-E/02, MEM-E/07, MEM-E/08, DT9, and 3D12) were tested on denatured, acid-treated, and natively folded (both beta sub(2)m-associated and beta sub(2)m-free) HLA-E molecules. Four distinct conformations were detected, including unusual, partially folded (and yet beta sub(2)m-free) heavy chains reactive with mAb DT9. In contrast with previous studies, epitope mapping and substitution scan on thousands of overlapping peptides printed on microchips revealed that mAbs MEM-E/02, MEM-E/07, and MEM-E/08 bind three distinct alpha 1 and alpha 2 domain epitopes. All three epitopes are linear since they span just 4-6 residues and are "hidden" in folded HLA-E heterodimers. They contain at least one HLA-E-specific residue that cannot be replaced by single substitutions with polymorphic HLA-A, HLA-B, HLA-C, HLA-F, and HLA-G residues. Finally, also the MEM-E/02 and 3D12 epitopes are spatially distinct. In summary, HLA-E-specific residues are dominantly immunogenic, but only when heavy chains are locally unfolded. Consequently, the available mAbs fail to selectively bind conformed HLA-E heterodimers, and HLA-E expression may have been inaccurately assessed in some previous oncology, reproductive immunology, virology, and transplantation studies.
Sprache
Englisch
Identifikatoren
ISSN: 0014-2980
eISSN: 1521-4141
DOI: 10.1002/eji.201545446
Titel-ID: cdi_proquest_miscellaneous_1709168372
Format
–
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