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Amplification of Autoimmune Response through Induction of Dendritic Cell Maturation in Inflamed Tissues¹

Kristin Melli^2,*, Rachel S. Friedman^2,, Ashley E. Martin^*, Erik B. Finger^*, Gang Miao^*, Gregory L. Szot, Matthew F. Krummel and Qizhi Tang^3,*

^* Department of Surgery, Department of Pathology, and University of California Diabetes Center, Department of Medicine, University of California, San Francisco, CA 94143

Dendritic cells (DCs) are essential in T cell-mediated destruction of insulin-producing β cells in the islets of Langerhans in type 1 diabetes. In this study, we investigated T cell induction of intra-islet DC maturation during the progression of the disease in both autoimmune-prone NOD and resistant C57BL/6 mice. We demonstrated steady-state capture and retention of unprocessed β cell-derived proteins by semimature intra-islet DCs in both mouse strains. T cell-mediated intra-islet inflammation induced an increase in CD40 and CD80 expression and processing of captured Ag by resident DCs without inducing the expression of the p40 subunit of IL-12/23. Some of the CD40^high intra-islet DCs up-regulated CCR7, and a small number of CD40^high DCs bearing unprocessed islet Ags were detected in the pancreatic lymph nodes in mice with acute intra-islet inflammation, demonstrating that T cell-mediated tissue inflammation augments migration of mature resident DCs to draining lymph nodes. Our results identify an amplification loop during the progression of autoimmune diabetes, in which initial T cell infiltration leads to rapid maturation of intra-islet DCs, their migration to lymph nodes, and expanded priming of more autoreactive T cells. Therapeutic interventions that intercept this process may be effective at halting the progression of type 1 diabetes.

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 study was supported by a Juvenile Diabetes Research Foundation research grant (to M.F.K. and Q.T.) and a grant from the National Institutes of Health (R21 AI66097 and R37 AI46643). R.S.F. was funded by the Larry L. Hillblom foundation.

² K.M. and R.S.F. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Qizhi Tang, Department of Surgery, University of California, San Francisco, Box 0780, 513 Parnassus Avenue, San Francisco, CA 94143-0780. E-mail address: Qizhi.Tang{at}ucsfmedctr.org

⁴ Abbreviations used in this paper: T1D, type 1 diabetes; CMTMR, 5(and 6)-(((4-chloromethyl)benzoyl)amino)tetramethylrhodamine; DAPI, 4',6'-diamidino-2-phenylindole; DC, dendritic cell; LN, lymph node; MIP, mouse insulin 1 promoter; mOVA, membrane-bound chicken OVA; PLN, pancreatic LN; RIP, rat insulin promoter; YFP, yellow fluorescent protein.

⁵ The online version of this article contains supplemental material.

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