DRα: Eβ heterodimers in DRA transgenic mice hinder expression of Eα:Eβ molecules and are more efficient in antigen presentation

S. Trembleau, P. Giacomini, J. C. Guery, A. Setini, J. Hammer, A. Sette, E. Appella, L. Adorini

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Abstract

HLA-DRA transgenic (tg) mice on H-2(d) background were constructed to study assembly, expression and function of DRα:Eβ class II heterodimers when an alternate Eα chain is available. Cytofluorimetric analysis and immunoprecipitation studies demonstrate that the majority (90%) of Eβ(d) molecules on class II-positive splenocytes from DRA-tg mice are associated with DRα rather than Eα chains. To characterize the functional role of the interspecies as compared with the wild-type I-E molecules, MHC restriction and T cell epitope immunodominance of synthetic peptides spanning the entire sequence of 65 kDa heat shock protein (hsp) from Mycobacterium tuberculosis were determined in hsp-primed DRA-tg and DBA/2 mice. A similar pattern of responsiveness was observed in both strains, but hsp epitopes recalled a higher response in DRA-tg as compared with DBA/2 mice. A panel of T cell hybridomas specific for two hsp peptides or a hen egg white lysozyme peptide presented by both DRα:Eβ(d) and Eα(d):Eβ(d) was studied in detail. Surprisingly, DRα:Eβ(d) dimers present these peptides more efficiently than Eα(d):Eβ(d), even when the TCR was selected in mice expressing only Eα(d):Eβ(d) molecules. The higher efficiency of antigen presentation by DRα:Eβ(d) dimers does not appear to depend on increased binding affinity for peptides, as demonstrated by competition for antigen presentation, nor on increased efficiency in the interaction with CD4 molecules. Rather, the higher efficiency of antigen presentation could be explained by a more effective ligand-TCR interaction. This is consistent with molecular modeling based on the class II structure, indicating that 16 out of 17 substitutions between the first domain of Eα(d) and DRα chains lie outside the peptide binding groove and are potentially available for interaction with the TCR.

Original languageEnglish
Pages (from-to)1927-1938
Number of pages12
JournalInternational Immunology
Volume7
Issue number12
Publication statusPublished - 1995

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Keywords

  • Antigen presentation
  • Hemixenogenic MHC class II
  • HLA-DRA transgenic mice

ASJC Scopus subject areas

  • Immunology
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Public Health, Environmental and Occupational Health
  • Neuropsychology and Physiological Psychology
  • Transplantation

Cite this

Trembleau, S., Giacomini, P., Guery, J. C., Setini, A., Hammer, J., Sette, A., Appella, E., & Adorini, L. (1995). DRα: Eβ heterodimers in DRA transgenic mice hinder expression of Eα:Eβ molecules and are more efficient in antigen presentation. International Immunology, 7(12), 1927-1938.