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Transcriptional Targeting of B Cells for Induction of Peripheral CD8 T Cell Tolerance¹

Melanie Werner-Klein^*, Christiane Dresch^*, Peggy Marconi and Thomas Brocker^2,*

^* Institute for Immunology, Ludwig-Maximilians-University, Munich, Germany; and Department of Experimental and Diagnostic Medicine, University of Ferrara, Ferrara, Italy

Several mechanisms are in place to neutralize autoimmune CD8 T cells by tolerance induction. Developing self-specific CD8 T cells are eliminated in the thymus by Ag-presenting epithelial and dendritic cells (DCs). However, CD8 T cells escaping thymic central tolerance can also be inactivated by tolerance mechanisms in peripheral organs. In contrast to DCs, the role of B cells in generating CD8 T cell tolerance is not well-characterized. To investigate this question in more detail, we transcriptionally targeted Ag to B cells using B cell-specific retroviral vectors in vivo. Although Ag expression could be detected in B cells of thymus, lymph nodes, and spleen, B cells were unable to induce central tolerance of CD8 thymocytes. In contrast, in peripheral organs, we could identify clonal deletion and functional inhibition (anergy) of CD8 T cells as tolerance-inducing mechanisms. Although Ag expressed by B cells was acquired and cross-presented by DCs, B cells were also sufficient to tolerize CD8 T cells directly. These findings suggest exploitation of B cells for Ag-specific immunotherapy of CD8 T cell-mediated autoimmune diseases.

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 Deutsche Forschungsgemeinschaft SFB 455 (to T.B.), the CAPES Foundation/Brazilian Ministry of Education (to C.D.), and the European Community FP6-2004-LIFESCIHEALTH-5, THOVLEN (to T.B. and P.M.).

² Address correspondence and reprint requests to Dr. Thomas Brocker, Institute for Immunology, Ludwig-Maximilians-University, Goethestrasse 31, D-80336 Munich, Germany. E-mail address: tbrocker{at}med.uni-muenchen.de

³ Abbreviations used in this paper: DC, dendritic cell; SIN, self interacting; RIP, rat insulin promoter; HSPC, hemopoietic stem and progenitor cell; sOVA, soluble OVA; BM-DC, bone marrow-derived DC; NTL, nontransgenic littermate.

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