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Lymphotoxin pathway directs thymic Aire expression

Nature Immunology volume 4, pages 1121–1127 (2003)Cite this article

Abstract

The autoimmune regulator Aire is a key mediator of central tolerance for peripherally restricted antigens. Its absence in human patients results in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. The cellular signals that regulate Aire expression are undefined. We show here that lymphotoxin signaling is necessary for the expression of Aire and its downstream target genes. The failure of Aire induction in the thymi of lymphotoxin-deficient and lymphotoxin-β receptor–deficient mice contributes to overt autoimmunity against self antigens normally protected by Aire. Conversely, stimulation of lymphotoxin-β receptor by agonistic antibody leads to increased expression of Aire and tissue-restricted antigens in both intact thymi and cultured thymic epithelial cell line. These findings define the essential cross-talk between thymocytes and thymic stroma that is required for central tolerance.

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Figure 1: Infiltration and inflammation in peripheral organs of Lta−/− and Ltbr−/− mice.
Figure 2: Lymphotoxin and LTβR regulate Aire expression in the thymus.
Figure 3: Induction of Aire expression with agonistic anti-LTβR.
Figure 4: Increased autoantibody production in Lta−/− and Ltbr−/− mice.
Figure 5: Autoimmune inflammation in lymphotoxin-deficient mice is lymphocyte autonomous.

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Acknowledgements

Supported in part by National Institutes of Health grants (HD-37104, AI 33068 and DK-58891). R.K.C. and J.C.L. were supported by a Medical Scientist National Research Service Award (5 T32 GM07281).

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Authors and Affiliations

  1. The Department of Pathology and Committee in Immunology, The University of Chicago, Chicago, 60637, Illinois, USA

    Robert K Chin, James C Lo, Oliver Kim, Sarah E Blink, Peter A Christiansen, Yang Wang & Yang-Xin Fu

  2. Institute of Medical Technology, Lenkkeilijankatu 6, University of Tampere, Tampere, 33014, Finland

    Pärt Peterson

  3. Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, 92121, California, USA

    Carl Ware

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  1. Robert K Chin
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Correspondence to Yang-Xin Fu.

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Chin, R., Lo, J., Kim, O. et al. Lymphotoxin pathway directs thymic Aire expression. Nat Immunol 4, 1121–1127 (2003). https://doi.org/10.1038/ni982

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