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IL-17A Inhibits the Expansion of IL-17A-Producing T Cells in Mice through "Short-Loop" Inhibition via IL-17 Receptor¹

Emily Smith^*, Matthew A. Stark^*,, Alexander Zarbock^*,¶,||, Tracy L. Burcin, Anthony C. Bruce, Devin Vaswani, Patricia Foley and Klaus Ley^2,||

^* Robert M. Berne Cardiovascular Research Center, Department of Molecular Physiology and Biological Physics, Department of Biomedical Engineering, and Office for the VP for Research and Graduate Studies, University of Virginia, Charlottesville, VA 22908; ^¶ Department of Anesthesiology and Critical Care Medicine, University of Muenster, Muenster, Germany; and ^|| Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037

IL-23 and IL-17A regulate granulopoiesis through G-CSF, the main granulopoietic cytokine. IL-23 is secreted by activated macrophages and dendritic cells and promotes the expansion of three subsets of IL-17A-expressing neutrophil-regulatory T (Tn) cells; CD4^–CD8^–β^low, CD4⁺CD8^–β⁺ (Th17), and ⁺ T cells. In this study, we investigate the effects of IL-17A on circulating neutrophil levels using IL-17R-deficient (Il17ra^–/–) mice and Il17ra^–/–Itgb2^–/– mice that lack both IL-17R and all four β₂ integrins. IL-17R deficiency conferred a reduction in neutrophil numbers and G-CSF levels, as did Ab blockade against IL-17A in wild-type mice. Bone marrow transplantation revealed that IL-17R expression on nonhemopoietic cells had the greatest effects on regulating blood neutrophil counts. Although circulating neutrophil numbers were reduced, IL-17A expression, secretion, and the number of IL-17A-producing Tn cells were elevated in Il17ra^–/– and Il17ra^–/–Itgb2^–/– mice, suggesting a negative feedback effect through IL-17R. The negative regulation of IL-17A-producing T cells and IL-17A and IL-17F gene expression through the interactions of IL-17A or IL-17F with IL-17R was confirmed in splenocyte cultures in vitro. We conclude that IL-17A regulates blood neutrophil counts by inducing G-CSF production mainly in nonhemopoietic cells. IL-17A controls the expansion of IL-17A-producing Tn cell populations through IL-17R.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health HL73361 (to K.L.), T32 GM 08715-01A1 (to M.A.S.), and Deutsche Forschungsgemeinschaft AZ428/2-1 (to A.Z.).

² Address correspondence and reprint requests to Dr. Klaus Ley, Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037. E-mail address: klaus{at}liai.org

³ Abbreviations used in this paper: WT, wild type; MLN, mesenteric lymph node; LP, lamina propria; BM, bone marrow; PMN, polymorphonuclear neutrophil.

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