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,
* Department of Immunology,
Department of Biological Structure, and
Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195; and
Department of Medical Genetics, University of Helsinki, Department of Molecular Medicine, National Public Health Institute, Biomedicum, Helsinki, Finland, and The Broad Institute, Massachusetts Institute of Technology, Boston, MA
The prevalent view of thymic epithelial differentiation and Aire activity holds that Aire functions in terminally differentiated medullary thymic epithelial cells (MTECs) to derepress the expression of structural tissue-restricted Ags, including pancreatic endocrine hormones. An alternative view of these processes has proposed that Aire functions to regulate the differentiation of immature thymic epithelial cells, thereby affecting tissue-restricted Ag expression and negative selection. In this study, we demonstrate that Aire impacts several aspects of murine MTECs and provide support for this second model. Expression of transcription factors associated with developmental plasticity of progenitor cells, Nanog, Oct4, and Sox2, by MTECs was Aire dependent. Similarly, the transcription factors that regulate pancreatic development and the expression of pancreatic hormones are also expressed by wild-type MTECs in an Aire-dependent manner. The altered transcriptional profiles in Aire-deficient MTECs were accompanied by changes in the organization and composition of the medullary epithelial compartment, including a reduction in the medullary compartment defined by keratin (K) 14 expression, altered patterns of K5 and K8 expression, and more prominent epithelial cysts. These findings implicate Aire in the regulation of MTEC differentiation and the organization of the medullary thymic compartment and are compatible with a role for Aire in thymic epithelium 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 the National Institutes of Health (Grants AI24137 and AI 059575). G.O.G. was supported in part by training grants from the National Institutes of Health and the Cancer Research Institute. L.P. received support from the European Union-funded project EURAPS (LSHM-CT-2005-005223) and the Center of Excellence of Complex Disease Genetics of the Academy of Finland.
2 Current address: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215.
3 Address correspondence and reprint requests to Dr. Andrew G. Farr, Department of Biology Structure, Box 35-7420, University of Washington, Seattle, WA 98195-7420. E-mail address: farr{at}u.washington.edu
4 Abbreviations used in this paper: TRA, tissue-restricted Ag; MTEC, medullary thymic epithelial cell; TE, thymic epithelium; WT, wild type; CMF, Ca2+- and Mg2+-free; RQ, relative quantity; Gip, glucose-dependent insulinotrophic peptide; LTR, lymphotoxin receptor; Epcam, epithelial cell adhesion molecule; HPRT, hypoxanthine phosphoribosyltransferase; UEA, U. europeus agglutinin.
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