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Lymphotoxin Pathway and Aire Influences on Thymic Medullary Epithelial Cells Are Unconnected¹

Department of Medicine, Section on Immunology and Immunogenetics, Joslin Diabetes Center, Brigham and Women’s Hospital; Harvard Medical School, Boston, MA 02215

The lymphotoxin pathway is critical for the development and maintenance of peripheral lymphoid organs. Mice with deficiencies in members of this pathway lack lymph nodes and Peyer’s patches and have abnormal spleen architecture. These animals also develop autoantibodies to and lymphocytic infiltrates of multiple organs, provoking speculation that the lymphotoxin pathway may play a role in central tolerance induction. Indeed, a series of reports has claimed that lymphotoxin signals control the expression of Aire, a transcriptional regulator that is expressed in medullary epithelial cells of the thymus, mediates ectopic transcription of genes encoding a variety of peripheral tissue Ags, and promotes clonal deletion of self-reactive thymocytes. However, one report argued that lymphotoxin signals regulate the composition and organization of the thymus, particularly of the medullary epithelial compartment. Herein, we resolve this controversy in favor of the latter view. The expression and function of Aire were unaffected in medullary epithelial cells of mice lacking either lymphotoxin receptor or the lymphotoxin -chain, and there was minimal overlap between the sets of genes controlled by Aire and lymphotoxin. Instead, both knockout lines showed abnormal medullary epithelial cell organization, and the line lacking the receptor had significantly fewer medullary epithelial cells. In short, the lymphotoxin pathway drives the developmental rather than selectional properties of thymic stromal cells.

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 Grant RO1 DK60027 and Young Chair funds (to D.M. and C.B.) and by Joslin’s National Institutes of Diabetes and Digestive and Kidney Diseases-funded Diabetes and Endocrinology Research Center core facilities. E.S.V. received support from National Institutes of Health Training Grant T32 DK07260 and D.H.D.G. received support from an Australian National Health and Medical Research Council C. J. Martin Overseas Biomedical Fellowship.

² Address correspondence and reprint requests to Dr. Christophe Benoist and Dr. Diane Mathis, Section on Immunology and Immunogenetics, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail address: cbdm{at}joslin.harvard.edu

³ Abbreviations used in this paper: LT, lymphotoxin; KO, knockout; PTA, peripheral tissue Ag; MEC, medullary epithelial cell; WT, wild type; CEC, cortical epithelial cell; K, keratin; UEA-1, Ulex europeaus agglutinin 1; FC, fold change; CII, type II collagen; RIP, rat insulin promoter; MFI, mean fluorescence intensity; DC, dendritic cell.

⁴ The online version of this article contains supplemental material.

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