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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-04-1036.
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Blood, 1 November 2002, Vol. 100, No. 9, pp. 3269-3278
IMMUNOBIOLOGY
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
From the Departments of Biological Structure and
Immunology, Howard Hughes Medical Institute, University of Washington,
Seattle, WA; and the Laboratory of Cellular and Molecular Biology,
National Cancer Institute, National Institutes of Health, Bethesda, MD.
Here we demonstrate that keratinocyte growth factor (KGF) and
FGFR2IIIb signaling can affect development and function of thymic epithelium (TE) and that   -lineage thymocytes contribute to
intrathymic levels of KGF. Thymocyte expression of KGF is
developmentally regulated, being undetectable in
CD3 48 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 major histocompatibility
complex (MHC), invariant chain (Ii), and cathepsin L (CatL) molecules
involved in thymocyte-positive selection and also stimulated expression
of the cytokines interleukin 6 (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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