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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-04-1036.
Submitted April 3, 2002
Accepted June 11, 2002
Regulation of thymic epithelium by keratinocyte growth factor
Matthew Erickson, Stanislaw Morkowski, Sophie Lehar, Geoffrey Gillard, Courtney Beers, James Dooley, Jeffrey S Rubin, Alexander Rudensky, and Andrew G Farr*
Department Biological Structure, University of Washington, Seattle, WA, USA
Department of Immunology, University of Washington, Seattle, WA, USA
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Department of Immunology, University of Washington, Seattle, WA, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
Department Biological Structure, University of Washington, Seattle, WA, USA; Department of Immunology, University of Washington, Seattle, WA, USA
* Corresponding author; email: farr{at}u.washington.edu.
Here we demonstrate that keratinocyte growth factor (KGF) and FGFR2IIIb signaling can affect development and function of thymic epithelium (TE) and that  ß-lineage thymocytes contribute to intrathymic levels of KGF. Thymocyte expression of KGF is developmentally regulated, being undetectable in CD3-4-8- thymocytes and expressed at highest levels by mature CD4 or CD8 thymocytes. Exposure of thymocyte-depleted fetal thymic lobes to KGF resulted in reduced thymic epithelial expression of class II MHC, invariant chain (Ii), and cathepsin L (CatL) molecules involved in thymocyte positive selection and also stimulated expression of the cytokines IL-6 and Thymic Stromal-derived Lymphopoietin (TSLP), while having little effect on IL-7 or stem cell factor expression. Within intact fetal thymic organ culture (FTOC), exogenous KGF impairs the generation of CD4 thymocytes. Two lines of evidence point to responsiveness of the medullary TE compartment to KGF and FGFR2IIIb signaling. First, the medullary compartment is expanded in intact FTOC exposed to KGF in vitro. Second, in the RAG-deficient thymus, where the thymocytes do not express detectable levels of KGF message, the hypoplastic medullary TE compartment can be expanded by administration of recombinant KGF in vivo. This expansion is accompanied by restoration of the normal profile of medullary TE-associated chemokine expression in the RAG2-/- thymus. Collectively, these findings point to a role for KGF and FGFR signaling in the development and function of thymic epithelium.
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