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Reduced Thymic Aire Expression and Abnormal NF-B2 Signaling in a Model of Systemic Autoimmunity¹

Anne L. Fletcher^*, Natalie Seach^*, Jessica J. Reiseger^*, Tamara E. Lowen^*, Maree V. Hammett^*, Hamish S. Scott and Richard L. Boyd^2,*

^* Immune Regeneration Laboratory, Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia; and Division of Molecular Pathology, the Institute of Medical and Veterinary Science and The Hanson Institute, Adelaide, and the School of Medicine at the University of Adelaide, Adelaide, South Australia, Australia

The thymic stromal niche normally directs the production and export of a self-tolerant T cell repertoire. Many models of spontaneous autoimmunity, however, develop thymic architectural abnormalities before disease onset. Although this is suspected to affect central tolerance induction, creating an autoimmune predisposition, in-depth analysis of the microenvironment within these thymi is lacking, such that the mechanisms and likely direct effects on the T cell repertoire are unknown or speculative. Here we show that NZB mice, the first described model for systemic autoimmunity, demonstrate a complex thymic phenotype, including a lack of the autoimmune regulator (Aire), early defects in thymic epithelial cell (TEC) expansion, and evidence for altered NF-B2 signaling. Analysis of medullary TEC revealed a numerical loss of the Aire-expressing MHC class II^high (mTEC-high) subset as well reduced Aire protein and mRNA per cell. RelB expression was also reduced, while chemokines CCL19 and CCL21 were increased. Unexpectedly, the proportion of cortex and medulla in the NZB mice was normal from 36 wk, despite worsening architectural abnormalities. These data show that the NZB defect is more complex than previously appreciated, segregating into early numerical TEC deficiencies that correct with age, late degeneration of the niche architecture that does not affect TEC number, and a persistent reduction in Aire and RelB expression per cell acquired upon mTEC-high differentiation.

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 funding from Norwood Immunology and the Australian Stem Cell Centre. H.S.S. was supported by National Health and Medical Research Council Fellowships 171601 and 461204, National Health and Medical Research Council Program Grants 257501 and 264573, and Eurothymaide, Sixth Framework Programme of the European Union.

² Address correspondence and reprint requests to Dr. Richard Boyd, Monash Immunology and Stem Cell Laboratories, Monash University, Wellington Road, Clayton, Victoria 3800, Australia. E-mail address: richard.boyd{at}med.monash.edu.au

³ Abbreviations used in this paper: cTEC, cortical TEC; Aire, autoimmune regulator; EpCAM: epithelial cell adhesion molecule; KNA, keratin-negative area; LT, lymphotoxin; RANKL, receptor activator of NF-B ligand; TEC, thymic epithelial cell; mTEC, medullary TEC; mTEC-high, medullary TEC expressing high levels of MHC class II; mTEC-low, mTEC expressing low levels of MHC class II; qPCR, quantitative PCR; TRA, tissue-restricted Ag; WT, wild type; UEA-1, Ulex europeaus agglutinin 1.