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

Dendritic cells can facilitate allograft survival and prevent autoimmunity via direct and indirect cell-mediated mecha-nisms. 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 inter-leukin (IL)-7. Unlike control dendritic cells, these den-dritic 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 ex-pressed significantly higher levels of IL-7R compared with levels in the CD4 CD25 subset, especially in diabetes-suppressive dendritic cell–administered NOD-scid recipi-ents. 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. Diabetes 55:158–170, 2006 Dendritic cells have been used in a variety ofembodiments to promote allograft survival andsuppress autoimmunity (1–4). A number ofmechanisms appear to be active in conferring these properties in vivo in these “immunoregulatory” dendritic cells (iDCs; diabetes-delaying dendritic cell em-bodiments). These mechanisms include attenuated coac-tivation through molecules of the B7 family, decreased production of proinflammatory interleukins like interleu