IL-17A Production by Renal γδ T Cells Promotes Kidney Injury in Crescentic GN.pdf

BASIC RESEARCH IL-17A Production by Renal gd T Cells Promotes Kidney Injury in Crescentic GN Jan-Eric Turner,* Christian Krebs,* Andre P. Tittel,† Hans-Joachim Paust,* Catherine Meyer-Schwesinger,* Sabrina B. Bennstein,* Oliver M. Steinmetz,* Immo Prinz,‡ Tim Magnus,§ Thomas Korn,| Rolf A.K. Stahl,* Christian Kurts,† and Ulf Panzer* *III Medizinische Klinik and §Department of Neurology, Universitätsklinikum Hamburg-Eppendorf, Germany; † Institutes of Molecular Medicine and Experimental Immunology, Bonn, Germany; ‡Institute of Immunology, Hannover Medical School, Hannover, Germany; and |Department of Neurology, Technical University Munich, Munich, Germany ABSTRACT The Th17 immune response appears to contribute to the pathogenesis of human and experimental crescentic GN, but the cell types that produce IL-17A in the kidney, the mechanisms involved in its induction, and the IL-17A–mediated effector functions that promote renal tissue injury are incompletely understood. Here, using a murine model of crescentic GN, we found that CD4+ T cells, gd T cells, and a population of CD3+CD42CD82gdT cell receptor2NK1.12 T cells all produce IL-17A in the kidney. A time course analysis identified gd T cells as a major source of IL-17A in the early phase of disease, before the first CD4+ Th17 cells arrived. The production of IL-17A by renal gd T cells depended on IL-23p19 signaling and retinoic acid–related orphan receptor-gt but not on IL-1b or IL-6. In addition, depletion of dendritic cells, which produce IL-23 in the kidney, reduced IL-17A production by renal gd T cells. Furthermore, the lack of IL-17A production in gd T cells, as well as the absence of all gd T cells, reduced neutrophil recruitment into the kidney and ameliorated renal injury. Taken together, these data suggest that gd T cells produce IL-17A in the kidney, induced by IL-23, promoting neutrophil recruitment, and contr