A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance

J Autoimmun. 2013 Feb;40:96-110. doi: 10.1016/j.jaut.2012.08.004. Epub 2012 Sep 29.

Abstract

Treatment with partial (p)MHC class II-β1α1 constructs (also referred to as recombinant T-cell receptor ligands - RTL) linked to antigenic peptides can induce T-cell tolerance, inhibit recruitment of inflammatory cells and reverse autoimmune diseases. Here we demonstrate a novel regulatory pathway that involves RTL binding to CD11b(+) mononuclear cells through a receptor comprised of MHC class II invariant chain (CD74), cell-surface histones and MHC class II itself for treatment of experimental autoimmune encephalomyelitis (EAE). Binding of RTL constructs with CD74 involved a previously unrecognized MHC class II-α1/CD74 interaction that inhibited CD74 expression, blocked activity of its ligand, macrophage migration inhibitory factor, and reduced EAE severity. These findings implicate binding of RTL constructs to CD74 as a key step in both antigen-driven and bystander T-cell tolerance important in treatment of inflammatory diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Differentiation, B-Lymphocyte / biosynthesis
  • Antigens, Differentiation, B-Lymphocyte / metabolism*
  • Autoimmune Diseases / immunology*
  • CD11b Antigen / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Histocompatibility Antigens Class II / biosynthesis
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism*
  • Immune Tolerance
  • Intramolecular Oxidoreductases
  • Macrophage Migration-Inhibitory Factors
  • Membrane Proteins
  • Mice
  • Monocytes / immunology*
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • T-Lymphocytes / immunology

Substances

  • Antigens, Differentiation, B-Lymphocyte
  • CD11b Antigen
  • Histocompatibility Antigens Class II
  • Macrophage Migration-Inhibitory Factors
  • Membrane Proteins
  • RTL342M protein, mouse
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • invariant chain
  • Intramolecular Oxidoreductases
  • Mif protein, mouse