Lymphotoxin pathway directs thymic Aire expression

Robert K. Chin, James C. Lo, Oliver Kim, Sarah E. Blink, Peter A. Christiansen, Pärt Peterson, Yang Wang, Carl Ware, Yang Xin Fu

Research output: Contribution to journalArticle

168 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1121-1127
Number of pages7
JournalNature immunology
Volume4
Issue number11
DOIs
StatePublished - Nov 1 2003

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Chin, R. K., Lo, J. C., Kim, O., Blink, S. E., Christiansen, P. A., Peterson, P., Wang, Y., Ware, C., & Fu, Y. X. (2003). Lymphotoxin pathway directs thymic Aire expression. Nature immunology, 4(11), 1121-1127. https://doi.org/10.1038/ni982