1. Regulation of thymic epithelium by keratinocyte growth factor
- Author
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Jeffrey S. Rubin, Geoffrey O. Gillard, Sophie M. Lehar, Andrew G. Farr, Matthew Erickson, Alexander Y. Rudensky, Stanislaw Morkowski, James Dooley, and Courtney Beers
- Subjects
CD4-Positive T-Lymphocytes ,medicine.medical_treatment ,Cathepsin L ,Fibroblast growth factor ,Biochemistry ,chemistry.chemical_compound ,Mice ,T-Lymphocyte Subsets ,Mice, Knockout ,Mice, Inbred BALB C ,Nuclear Proteins ,Hematology ,Cell biology ,Fetal Thymic Organ Culture ,DNA-Binding Proteins ,Thymocyte ,Cysteine Endopeptidases ,Cytokines ,Fibroblast Growth Factor 1 ,Female ,Fibroblast Growth Factor 2 ,Keratinocyte growth factor ,Signal Transduction ,medicine.medical_specialty ,Thymic stromal lymphopoietin ,Fibroblast Growth Factor 7 ,Recombinant Fusion Proteins ,Immunology ,Clonal Deletion ,Thymus Gland ,Biology ,Organ Culture Techniques ,Thymic Stromal Lymphopoietin ,Internal medicine ,medicine ,Animals ,Humans ,Lymphopoiesis ,Receptor, Fibroblast Growth Factor, Type 2 ,Interleukin-6 ,Growth factor ,Histocompatibility Antigens Class II ,Epithelial Cells ,Cell Biology ,Cathepsins ,Receptors, Fibroblast Growth Factor ,Antigens, Differentiation, B-Lymphocyte ,Fibroblast Growth Factors ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Stromal Cells ,Lysosomes ,Fibroblast Growth Factor 10 ,CD8 - Abstract
Here we demonstrate that keratinocyte growth factor (KGF) and FGFR2IIIb signaling can affect development and function of thymic epithelium (TE) and that αβ-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 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.
- Published
- 2002