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B Cells Drive Early T Cell Autoimmunity In Vivo prior to Dendritic Cell-Mediated Autoantigen Presentation¹

Jun Yan^2,*, Bohdan P. Harvey^*, Renelle J. Gee^*, Mark J. Shlomchik and Mark J. Mamula^3,*

^* Section of Rheumatology, Department of Internal Medicine, and Department of Laboratory Medicine and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520

Both B cells and dendritic cells (DCs) have been implicated as autoantigen-presenting cells in the activation of self-reactive T cells. However, most self-proteins are ubiquitously and/or developmentally expressed, making it difficult to determine the source and the exposure of autoantigens to APCs in a controlled manner. In this study, we have used an Ig transgenic mouse model to examine the mechanisms by which B cells and other APCs acquire and present lupus autoantigens in vivo. Targeting a lupus autoantigen, the small nuclear ribonucleoprotein particle D protein, to the BCR activates autoreactive T cells in the periphery. Our in vivo studies demonstrate that autoantigen-specific B cells, when present in the repertoire, are the first subset of APCs to capture and present self-proteins for activating T cells. Thereafter, DCs acquire self-Ag and become effective APCs for stimulating the same subsets of autoreactive T cells. This mechanism provides one explanation of how early steps in autoimmunity can focus responses, via BCR, at a small group of self-proteins among the total milieu of intracellular self-proteins. Subsequently, DCs and other professional APCs may then amplify and perpetuate the autoimmune T cell response.

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 National Institutes of Health Grants AI-36529 and AR-41032 (to M.J.M.) and by the Arthritis Foundation (to J.Y.).

² Current address: Tumor Immunobiology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202.

³ Address correspondence and reprint requests to Dr. Mark J. Mamula, Yale University School of Medicine, 300 Cedar Street, TAC S-525, P.O. Box 208031, New Haven, CT 06520-8031. E-mail address: mark.mamula{at}yale.edu

⁴ Abbreviations used in this paper: snRNP, small nuclear ribonucleoprotein particle; NP, nitrophenyl; DC, dendritic cell.

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