Amplification of autoimmune response through induction of dendritic cell maturation in inflamed tissues

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

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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 CD40high 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.

Original languageEnglish (US)
Pages (from-to)2590-2600
Number of pages11
JournalJournal of Immunology
Volume182
Issue number5
DOIs
StatePublished - Mar 1 2009

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