MMTV superantigens coerce an unconventional topology between the TCR and MHC class II

J Immunol. 2014 Feb 15;192(4):1896-906. doi: 10.4049/jimmunol.1203130. Epub 2014 Jan 22.

Abstract

Mouse mammary tumor virus superantigens (vSAGs) are notorious for defying structural characterization, and a consensus has yet to be reached regarding their ability to bridge the TCR to MHC class II (MHCII). In this study, we determined the topology of the T cell signaling complex by examining the respective relation of vSAG7 with the MHCII molecule, MHCII-associated peptide, and TCR. We used covalently linked peptide/MHCII complexes to demonstrate that vSAG presentation is tolerant to variation in the protruding side chains of the peptide, but can be sensitive to the nature of the protruding N-terminal extension. An original approach in which vSAG was covalently linked to either MHCII chain confirmed that vSAG binds outside the peptide binding groove. Also, whereas the C-terminal vSAG segment binds to the MHCII α-chain in a conformation-sensitive manner, the membrane-proximal N-terminal domain binds the β-chain. Because both moieties of the mature vSAG remain noncovalently associated after processing, our results suggest that vSAG crosslinks MHCII molecules. Comparing different T cell hybridomas, we identified key residues on the MHCII α-chain that are differentially recognized by the CDR3β when engaged by vSAG. Finally, we show that the highly conserved tyrosine residue found in the vSAg TGXY motif is required for T cell activation. Our results reveal a novel SAG/MHCII/TCR architecture in which vSAGs coerce a near-canonical docking between MHCII and TCR that allows eschewing of traditional CDR3 binding with the associated peptide in favor of MHCII α-chain binding. Our findings highlight the plasticity of the TCR CDRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral / immunology*
  • Binding Sites / immunology
  • HEK293 Cells
  • HeLa Cells
  • Histocompatibility Antigens Class II / immunology*
  • Humans
  • Jurkat Cells
  • Lymphocyte Activation / immunology
  • Mammary Tumor Virus, Mouse / immunology*
  • Protein Binding / immunology
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • Signal Transduction / immunology
  • Superantigens / immunology*
  • T-Lymphocytes / immunology

Substances

  • Antigens, Viral
  • Histocompatibility Antigens Class II
  • Receptors, Antigen, T-Cell, alpha-beta
  • Superantigens