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* Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Australia;
Bernard O’Brien Institute of Microsurgery, Fitzroy;
Division of Molecular Medicine, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia;
Queensland Institute of Medical Research, Herston, Queensland, Australia;
¶ Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, CA 92037; and
|| Joslin Diabetes Center, Boston, MA 02215
Medullary thymic epithelial cells (mTEC) play an important and unique role in central tolerance, expressing tissue-restricted Ags (TRA) which delete thymocytes autoreactive to peripheral organs. Since deficiencies in this cell type or activity can lead to devastating autoimmune diseases, it is important to understand the factors which regulate mTEC differentiation and function. Lymphotoxin (LT) ligands and the LTβR have been recently shown to be important regulators of mTEC biology; however, the precise role of this pathway in the thymus is not clear. In this study, we have investigated the impact of this signaling pathway in greater detail, focusing not only on mTEC but also on other thymic stromal cell subsets. LTβR expression was found in all TEC subsets, but the highest levels were detected in MTS-15+ thymic fibroblasts. Rather than directing the expression of the autoimmune regulator Aire in mTEC, we found LTβR signals were important for TRA expression in a distinct population of mTEC characterized by low levels of MHC class II (mTEClow), as well as maintenance of MTS-15+ fibroblasts. In addition, thymic stromal cell subsets from LT-deficient mice exhibit defects in chemokine production similar to that found in peripheral lymphoid organs of Lta–/– and Ltbr–/– mice. Thus, we propose a broader role for LT
1β2-LTβR signaling in the maintenance of the thymic microenvironments, specifically by regulating TRA and chemokine expression in mTEClow for efficient induction of central tolerance.
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 grants from the Australian National Health and Medical Research Council and funding from Norwood Immunology Ltd. and the Australian Stem Cell Centre (to R.L.B.). D.H.D.G. was supported by a National Health and Medical Research Council C. J. Martin Overseas Training Fellowship. 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, 6th Framework Programme of the European Union.
2 N.S. and T.U. contributed equally to this work.
3 Current address: Department of Plastic and Reconstructive Surgery, Innsbruck Medical University Anichstrasse, 35 A- 6020 Innsbruck, Austria.
4 Current address: Division of Molecular Pathology, Institute of Medical and Veterinary Science and anson Institute, Box 14 Rundle Mall Post Office, Adelaide, South Australia 5000, Australia.
5 D.H.D.G. and R.L.B. share senior authorship.
6 Address correspondence and reprint requests to Dr. Richard Boyd, Monash Immunology and Stem Cell Centre, Monash University, Wellington Road, Clayton, Victoria, Australia 3800. E-mail address: richard.boyd{at}med.monash.edu.au
7 Abbreviations used in this paper: TSC, thymic stromal cell; Aire, autoimmune regulator; DC, dendritic cell; TRA, tissue-restricted Ag; LT, lymphotoxin; TEC, thymic epithelial cell; cTEC, cortical TEC; mTEC, medullary TEC; MHCII, MHC class II; wt, wild type; UEA-1, Ulex europeaus agglutinin 1; EpCAM, epithelial cell adhesion molecule; PDGFR, platelet-derived growth factor receptor ; FGF, fibroblast growth factor; LTBR-ag, LTBR agonist.
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  A. L. Fletcher, N. Seach, J. J. Reiseger, T. E. Lowen, M. V. Hammett, H. S. Scott, and R. L. Boyd Reduced Thymic Aire Expression and Abnormal NF-{kappa}B2 Signaling in a Model of Systemic Autoimmunity J. Immunol., March 1, 2009; 182(5): 2690 - 2699. [Abstract] [Full Text] [PDF]
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