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

Arthur A Vandenbark; Roberto Meza-Romero; Gil Benedek; Shayne Andrew; Jianya Huan; Yuan K Chou; Abigail C Buenafe; Rony Dahan; Yoram Reiter; Jeffery L Mooney; Halina Offner; Gregory G Burrows

doi:10.1016/j.jaut.2012.08.004

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.

Authors

Arthur A Vandenbark^#^{1

2

3

4

5}, Roberto Meza-Romero^#^{2

3}, Gil Benedek^#^{2

3

4}, Shayne Andrew^{2

3}, Jianya Huan³, Yuan K Chou^{3

4}, Abigail C Buenafe³, Rony Dahan⁶, Yoram Reiter⁶, Jeffery L Mooney³, Halina Offner^{2

4

7}, Gregory G Burrows^{3

4

8

9}

Affiliations

¹ Research Service, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.
² Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.
³ Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.
⁴ Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
⁵ Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239, USA.
⁶ Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
⁷ Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
⁸ Department of Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.
⁹ Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.

^# Contributed equally.

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.

Published by Elsevier Ltd.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding