TCR-like antibodies distinguish conformational and functional differences in two- versus four-domain auto reactive MHC class II-peptide complexes

Rony Dahan, Moran Tabul, Yuan K. Chou, Roberto Meza-Romero, Shayne Andrew, Adolph J. Ferro, Gregory G. Burrows, Halina Offner, Arthur A. Vandenbark, Yoram Reiter

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Antigen-presenting cell-associated four-domain MHC class II (MHC-II) molecules play a central role in activating autoreactive CD4+ T cells involved in multiple sclerosis (MS) and type 1 diabetes (T1D). In contrast, two-domain MHC-II structures with the same covalently attached self-peptide (recombinant T-cell receptor ligands (RTLs)) can regulate pathogenic CD4+ T cells and reverse clinical signs of experimental autoimmune diseases. RTL1000, which is composed of the β1α1 domains of human leukocyte antigen (HLA)-DR2 linked to the encephalitogenic human myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, was recently shown to be safe and well tolerated in a phase I clinical trial in MS. To evaluate the opposing biological effects of four- versus two-domain MHC-II structures, we screened phage Fab antibodies (Abs) for the neutralizing activity of RTL1000. Five different TCR-like Abs were identified that could distinguish between the two- versus four-domain MHC-peptide complexes while the cognate TCR was unable to make such a distinction. Moreover, Fab detection of native two-domain HLA-DR structures in human plasma implies that there are naturally occurring regulatory MHC-peptide complexes. These results demonstrate for the first time distinct conformational determinants characteristic of activating versus tolerogenic MHC-peptide complexes involved in human autoimmunity.

Original languageEnglish (US)
Pages (from-to)1465-1479
Number of pages15
JournalEuropean Journal of Immunology
Volume41
Issue number5
DOIs
StatePublished - May 2011

Keywords

  • Autoimmunity
  • Immune tolerance
  • MHC class II
  • Recombinant antibodies

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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