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Dendritic Cells in Human Thymus and Periphery Display a Proinsulin Epitope in a Transcription-Dependent, Capture-Independent Fashion ¹

Carlos A. Garcia^2,*, Kamalaveni R. Prabakar^2,*, Juan Diez^2,*, Zhu Alexander Cao^||, Gloria Allende^*, Markus Zeller^*, Rajpreet Dogra^*, Armando Mendez^*,, Eliot Rosenkranz^,¶, Ulf Dahl^*, Camillo Ricordi^*,,, Douglas Hanahan^|| and Alberto Pugliese^3,*,,

^* Immunogenetics Program and Cell Transplant Center, Diabetes Research Institute, Department of Medicine, Department of Immunology and Microbiology, Department of Surgery, and ^¶ Division of Cardiothoracic Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136; and ^|| Department of Biochemistry and Biophysics and Diabetes Center, University of California, San Francisco Comprehensive Cancer Center, San Francisco, CA 94143

The natural expression of tissue-specific genes in the thymus, e.g., insulin, is critical for self-tolerance. The transcription of tissue-specific genes is ascribed to peripheral Ag-expressing (PAE) cells, which discordant studies identified as thymic epithelial cells (TEC) or CD11c⁺ dendritic cells (DC). We hypothesized that, consistent with APC function, PAE-DC should constitutively display multiple self-epitopes on their surface. If recognized by Abs, such epitopes could help identify PAE cells to further define their distribution, nature, and function. We report that selected Abs reacted with self-epitopes, including a proinsulin epitope, on the surface of CD11c⁺ cells. We find that Proins⁺CD11c⁺ PAE cells exist in human thymus, spleen, and also circulate in blood. Human thymic Proins⁺ cells appear as mature DC but express CD8, CD20, CD123, and CD14; peripheral Proins⁺ cells appear as immature DC. However, DC derived in vitro from human peripheral blood monocytes include Proins⁺ cells that uniquely differentiate and mature into thymic-like PAE-DC. Critically, we demonstrate that human Proins⁺CD11c⁺ cells transcribe the insulin gene in thymus, spleen, and blood. Likewise, we show that mouse thymic and peripheral CD11c⁺ cells transcribe the insulin gene and display the proinsulin epitope; moreover, by using knockout mice, we show that the display of this epitope depends upon insulin gene transcription and is independent of Ag capturing. Thus, we propose that PAE cells include functionally distinct DC displaying self-epitopes through a novel, transcription-dependent mechanism. These cells might play a role in promoting self-tolerance, not only in the thymus but also in the periphery.

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