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Constitutive Expression of B7-1 on B Cells Uncovers Autoimmunity toward the B Cell Compartment in the Nonobese Diabetic Mouse¹

Hélène Bour-Jordan^*, Benoit L. Salomon, Heather L. Thompson^*, Rex Santos^*, Abul K. Abbas and Jeffrey A. Bluestone^2,*

^* University of California, San Francisco Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143; Centre National de la Recherche Scientifique/Université Pierre et Marie Curie Unité Mixte de Recherche 7087, Hôpital Pitié-Salpêtrière, Paris, France; and Department of Pathology, University of California, School of Medicine, San Francisco, CA 94143

The NOD mouse is an invaluable model for the study of autoimmune diabetes. Furthermore, although less appreciated, NOD mice are susceptible to other autoimmune diseases that can be differentially manifested by altering the balance of T cell costimulatory pathways. In this study, we show that constitutively expressing B7-1 on B cells (NOD-B7-1B-transgenic mice) resulted in reduced insulitis and completely protected NOD mice from developing diabetes. Furthermore, B7-1 expression led to a dramatic reduction of the B cell compartment due to a selective deletion of follicular B cells in the spleen, whereas marginal zone B cells were largely unaffected. B cell depletion was dependent on B cell specificity, mediated by CD8⁺ T cells, and occurred exclusively in the autoimmune-prone NOD background. Our results suggest that B cell deletion was a consequence of the specific activation of autoreactive T cells directed at peripheral self Ags presented by maturing B cells that expressed B7-1 costimulatory molecules. This study underscores the importance of B7 costimulatory molecules in controlling the amplitude and target of autoimmunity in genetically prone individuals and has important implications in the use of costimulatory pathway antagonists in the treatment of human 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 research grants from the National Institutes of Health (AI-50834, P30 DK63720, U19 AI056388) and an American Diabetes Association mentor-based award.

² Address correspondence and reprint requests to Dr. Jeffrey A. Bluestone, University of California Diabetes Center, University of California, Box 0540, 513 Parnassus Avenue, San Francisco, CA 94143-0540. E-mail address: jbluest{at}diabetes.ucsf.edu

³ Abbreviations used in this paper: Treg, regulatory T cell; DAPI, 4',6'-diamidino-2-phenylindole, dilactate; FO, follicular; HEL, hen egg lysozyme; MZ, marginal zone; SAV, streptavidin; Tg, transgenic.

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