"Chemical analogues" of HLA-DM can induce a peptide-receptive state in HLA-DR molecules

The Journal of Biological Chemistry
Viviana Marin-EstebanOlaf Rötzschke

Abstract

We had recently identified small molecular compounds that are able to accelerate the ligand exchange reactions of HLA-DR molecules. Here we show that this acceleration is due to the induction of a "peptide-receptive" state. Dissociation experiments of soluble HLA-DR2.CLIP (class II-associated invariant chain peptide) complex and peptide-binding studies with "nonreceptive" empty HLA-DR1 and -DR2 molecules revealed that the presence of a small phenolic compound carrying an H-bond donor group (-OH) results in the drastic increase of both off- and on-rates. The rate-limiting step for ligand exchange, the transition of the major histocompatibility complex molecule from a nonreceptive into the receptive state, is normally mediated by interaction with the chaperone HLA-DM. In this respect, the effect of small molecules resembles that of the natural catalyst, except that they are still active at neutral pH. These "chemical analogues" of HLA-DM can therefore modulate the response of CD4+ T cells by editing the antigen composition of surface-bound class II major histocompatibility complex on living antigen-presenting cells.

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Citations

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Dec 3, 2010·Trends in Immunology·Cristina C ClementLaura Santambrogio
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May 2, 2009·Angewandte Chemie·Andreas SchlundtChristian Freund
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May 28, 2019·Frontiers in Immunology·Laura SantambrogioVictor H Engelhard

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