Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes

Frances C. Hall, Joshua D. Rabinowitz, Robert Busch, Kevin C. Visconti, Michael Belmares, Namrata S. Patil, Andrew P. Cope, Salil Patel, Harden M. McConnell, Elizabeth D. Mellins, Grete Sonderstrup

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49 Scopus citations

Abstract

Immunodominant T cell epitopes from the autoantigen human cartilage glycoprotein 39 have previously been mapped in the context of HLA-DR*0401 and *0402, using mice expressing HLA-DR4 transgenes. We measured the dissociation rates of these epitopes from soluble recombinant DR*0401 and DR*0402 to assess the relationship between peptide/HLA-DR4 kinetic stability and immunogenicity. Experiments were performed at endosomal pH (5.5) and at cell surface pH (7), in the absence and presence of soluble recombinant HLA-DM (sDM). All (4/4) immunodominant peptide/HLA-DR complexes exhibit dissociation half-times of 1 h to several days. In contrast, most (3/4) non-immunodominant complexes dissociate with half-times <30 min under at least one of these conditions. Interestingly, a complex which is stable except in the presence of HLA-DM at pH 5.5 is immunogenic only following peptide immunization, while a complex which is stable at acidic but not at neutral pH, is non-immunogenic following either whole protein or peptide immunization. These data indicate that kinetic stability of peptide/MHC complexes in vivo is a key determinant of immunogenicity.

Original languageEnglish (US)
Pages (from-to)662-670
Number of pages9
JournalEuropean Journal of Immunology
Volume32
Issue number3
DOIs
StatePublished - 2002
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Keywords

  • Antigen
  • Antigen presentation
  • Epitope
  • MHC
  • Peptide
  • T lymphocyte

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    Hall, F. C., Rabinowitz, J. D., Busch, R., Visconti, K. C., Belmares, M., Patil, N. S., Cope, A. P., Patel, S., McConnell, H. M., Mellins, E. D., & Sonderstrup, G. (2002). Relationship between kinetic stability and immunogenicity of HLA-DR4/peptide complexes. European Journal of Immunology, 32(3), 662-670. https://doi.org/10.1002/1521-4141(200203)32:3<662::AID-IMMU662>3.0.CO;2-5