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* Monash Immunology and Stem Cell Laboratories, Monash University, Clayton, Victoria, Australia;
Department of Biochemistry, Melbourne University, Parkville, Melbourne, Australia; and
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543
T cell differentiation in the thymus is dependent upon signals from thymic stromal cells. Most studies into the nature of these signals have focused only on the support provided by the thymic epithelium, but there is an emerging view that other stromal cells such as mesenchymal fibroblasts may also be involved. Study of the latter has been hindered by a lack of appropriate markers, particularly those allowing their isolation. In this study, we describe a new surface marker of thymic stroma, MTS-15, and demonstrate its specificity for fibroblasts and a subset of endothelial cells. Coculture experiments showed that the determinant could be transferred between cells. Extensive biochemical analysis demonstrated that the Ag bound by MTS-15 was the glycosphingolipid Forssman determinant, consistent with the distribution observed. Transcriptional analysis of purified MTS-15+ thymic fibroblasts revealed a unique expression profile for a number of chemokines and growth factors important to thymocyte and epithelial cell development. In a model of cyclophosphamide-induced thymic involution and regeneration, fibroblasts were found to expand extensively and express growth factors important to epithelial proliferation and increased T cell production just before thymic regeneration. Overall, this study identifies a useful marker of thymic fibroblasts and highlights this subpopulation as a key player in thymic function by virtue of their support of both thymocytes and epithelial cells.
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 and the Australian Stem Cell Centre.
2 Current address: Joslin Diabetes Center, One Joslin Place, Boston, MA, 02215
3 Address correspondence and reprint requests to Dr. Richard Boyd, Monash Immunology and Stem Cell Laboratories, Monash University, Wellington Road, Clayton, Victoria, Australia. E-mail address: Richard.boyd{at}med.monash.edu.au
4 Abbreviations used in this paper: TN, triple negative; E, embryonic day; EGCase II, endoglycoceramidase II; FGF, fibroblast growth factor; Gal, galactose; GalNAc, N-acetylgalactosamine; Glc, glucose; HPTLC, high performance TLC; MTS, mouse thymic stroma; PDGFR
, platelet derived growth factor receptor -chain; SCF, stem cell factor; TEC, thymic epithelial cell; cTEC, cortical TEC; mTEC, medullary TEC.
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