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T-Lineage Cells Require the Thymus but Not V(D)J Recombination to Produce IL-17A and Regulate Granulopoiesis In Vivo¹

Emily Smith,^2* Sibylle von Vietinghoff,² Matthew A. Stark,^* Alexander Zarbock,^* John M. Sanders,^* Amanda Duley,^¶ Jesus Rivera-Nieves,^|| Timothy P. Bender,^¶ and Klaus Ley³

^*Robert M. Berne Cardiovascular Research Center and Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908; Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037; Department of Anesthesiology and Critical Care Medicine, University of Münster, Münster, Germany; ^¶Department of Microbiology, University of Virginia, Charlottesville, VA 22908; and ^||Mucosal Inflammation Program, University of Colorado Health Sciences Center, Denver, CO 80206

IL-17A and IL-17F regulate granulopoiesis and are produced by memory T cells. Rag1^–/– recombinase-activating gene-deficient mice cannot produce mature T cells but maintain normal neutrophil counts. Athymic nude mice are neutropenic or have near-normal neutrophil counts, depending on the prevailing intestinal flora, and do not produce IL-17A. By contrast, thymi from Rag1^–/– mice contain as much IL-17A as those from wild-type (WT) mice. IL-17A-producing cells are found in the double negative DN1 compartment of the Rag1^–/– thymus and express intracellular CD3. These cells colonize the spleen and mesenteric lymph node and secrete IL-17A in vitro following stimulation with IL-23 at a level similar to that of WT splenocytes. Adoptively transferred Rag1^–/– or WT thymocytes correct neutrophil counts in neutropenic nude mice. We conclude that the development of IL-17A-producing T-lineage cells requires an intact thymic epithelium, but not V(D)J recombination.

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 National Institutes of Health Grants HL73361 (to K.L.), T32 GM08715 (to M.A.S.), and Deutsche Forschungsgemeinschaft Grants AZ428/2-1 (to A.Z.) and VI508/1-1 (to S.v.V.).

² E.S. and S.v.V. contributed equally to this work.

³ 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

⁴ Abbreviations used in this paper: WT, wild type; BM, bone marrow; DN, double negative; f, floxed; LP, lamina propria; LTi, lymphoid tissue inducer; MLN, mesenteric lymph node.

⁵ The online version of this article contains supplemental material.