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Interleukin-7 Is a Survival Factor for CD4⁺ CD25⁺ T-Cells and Is Expressed by Diabetes-Suppressive Dendritic Cells

¹ Department of Pediatrics, Division of Immunogenetics, Diabetes Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
² Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Nick Giannoukakis, PhD, Department of Pathology, University of Pittsburgh School of Medicine, Diabetes Institute, Rangos Research Center, 3460 Fifth Ave., Pittsburgh, PA 15213. E-mail: ngiann1{at}pitt.edu

Abbreviations: CFSE, carboxyfluorescein ester; FACS, fluorescence-activated cell sorter; iDC, immunoregulatory dendritic cell; IL, interleukin; STAT, signal transducer and activation of transcription; Treg, T regulatory cell

Dendritic cells can facilitate allograft survival and prevent autoimmunity via direct and indirect cell-mediated mechanisms. Recent studies demonstrate that immunoregulatory dendritic cells (iDCs) confer immune hyporesponsiveness in part through CD4⁺ CD25⁺ T regulatory cells (Tregs). Herein, we provide evidence to support the hypothesis that dendritic cells derived from NOD mice and engineered ex vivo to exhibit suppressed expression of the CD40, CD80, and CD86 costimulatory molecules motivate an increase in the prevalence of regulatory CD4⁺ CD25⁺ T-cells via interleukin (IL)-7. Unlike control dendritic cells, these dendritic cells expressed significant levels of IL-7. Exogenous addition of IL-7 to NOD T-cells did not promote expansion or proliferation, but instead selectively maintained the number of CD4⁺ CD25⁺ T-cells by inhibiting activation of apoptosis in these cells. In vitro, IL-7 receptor -chain (IL-7R) was expressed at significantly higher levels on CD4⁺ CD25⁺ T-cells compared with CD4⁺ CD25^– T-cells irrespective of resting or stimulated state. In vivo, CD4⁺ CD25⁺ T-cells obtained from NOD-scid mice reconstituted with ex vivo engineered iDCs and NOD splenocytes expressed significantly higher levels of IL-7R compared with levels in the CD4⁺ CD25^– subset, especially in diabetes-suppressive dendritic cell–administered NOD-scid recipients. Taken together, our data suggest a novel mechanism by which iDCs delay autoimmunity through the CD4⁺ CD25⁺ Treg pathway and suggest IL-7 as a survival factor for these putative Tregs, which express the -chain of its receptor at considerably higher levels than CD4⁺ CD25^– T-cells.

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