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B Cells Induce Tolerance by Presenting Endogenous Peptide-IgG on MHC Class II Molecules via an IFN--Inducible Lysosomal Thiol Reductase-Dependent Pathway¹

Yan Su^*,, Gregory Carey^*,, Maja Mari and David W. Scott^2,*

^* Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland, School of Medicine, Baltimore, MD 21201; Immunology Program, Institute for Biomedical Sciences, George Washington University, Washington DC 20037; Program in Oncology, Greenbaum Cancer Center, University of Maryland, School of Medicine, Baltimore, MD 21201; and Department of Microbiology and Immunology, Georgetown University School of Medicine, Washington DC 20057

We have previously demonstrated that splenic B cells, transduced with peptide-IgG fusion proteins, are efficient tolerogenic APCs in vivo. Specific hyporesponsiveness to epitopes encoded in the peptide-IgG fusion protein has been achieved to over one dozen Ags, and clinical efficacy has been established in animal models for several autoimmune diseases and hemophilia. Previous studies also demonstrated that tolerance in this system requires MHC class II expression by the transduced B cells. Yet, the mechanisms of this B cell tolerogenic processing pathway remain unclear. In this study, we show that MHC class II molecules on tolerogenic B cells present epitopes derived from endogenous, but not exogenous (secreted), peptide-IgG fusion protein. These class II epitopes from the IgG fusion protein are processed in lysosomes/endosomes in an IFN--inducible lysosomal thiol reductase-dependent manner. We suggest that the MHC class II presentation of endogenously produced fusion protein epitopes represents a novel mechanism for tolerance induced by peptide-IgG-transduced B cells. An understanding of this process might provide insights into central and peripheral tolerance induced by other professional and nonprofessional APCs.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from National Institutes of Health (RO1 AI035622-10).

² Address correspondence and reprint requests to Dr. David W. Scott, Departments of Surgery and Microbiology and Immunology, and Center for Vascular and Inflammatory Diseases, University of Maryland, School of Medicine, Baltimore, MD 21201. E-mail address: davscott{at}som.umaryland.edu

³ Abbreviations used in this paper: Lamp, lysosome-associated membrane protein; ER, endoplasmic reticulum; GILT, IFN--inducible lysosomal thiol reductase; HEL, hen egg lysozyme; hsc, heat shock cognate protein; KO, knockout; LN, lymph node; RFP, red fluorescence protein; WT, wild type; SNARF, seminaphtharhodafluor.