IL-12 Drives IFN-γ-Dependent Autoimmune Kidney Disease in MRL-FaslprMice

Abstract

AbstractIL-12 is secreted by kidney tubular epithelial cells in autoimmune MRL-Faslpr mice before renal injury and increases with advancing disease. Because IL-12 is a potent inducer of IFN-γ, the purpose of this study was to determine whether local provision of IL-12 elicits IFN-γ-secreting T cells within the kidney, which, in turn, incites injury in MRL-Faslpr mice. We used an ex vivo retroviral gene transfer strategy to construct IL-12-secreting MRL-Faslpr tubular epithelial cells (IL-12 “carrier cells”), which were implanted under the kidney capsule of MRL-Faslpr mice before renal disease for a sustained period (28 days). IL-12 “carrier cells” generated intrarenal and systemic IL-12. IL-12 fostered a marked, well-demarcated accumulation of CD4, CD8, and double negative (CD4−CD8− B220+) T cells adjacent to the implant site. We detected more IFN-γ-producing T cells (CD4 > CD8 > CD4−CD8− B220+) at 28 days (73 ± 14%) as compared with 7 days (20 ± 8%) after implanting the IL-12 “carrier cells;” the majority of these cells were proliferating (60–70%). By comparison, an increase in systemic IL-12 resulted in a diffuse acceleration of pathology in the contralateral (unimplanted) kidney. IFN-γ was required for IL-12-incited renal injury, because IL-12 “carrier cells” failed to elicit injury in MRL-Faslpr kidneys genetically deficient in IFN-γ receptors. Furthermore, IFN-γ “carrier cells” elicited kidney injury in wild-type MRL-Faslpr mice. Taken together, IL-12 elicits autoimmune injury by fostering the accumulation of IFN-γ-secreting CD4, CD8, and CD4−CD8− B220+ T cells within the kidney, which, in turn, promote a cascade of events culminating in autoimmune kidney disease in MRL-Faslpr mice.