Regulation of thymic epithelium by keratinocyte growth factor.
Here we demonstrate that keratinocyte growth factor (KGF) and FGFR2IIIb signaling can affect development and function of thymic epithelium (TE) and that alphabeta-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.
Erickson
Matthew
M
Department of Biological Structure, School of Medicine, Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195-7420, USA.
Morkowski
Stanislaw
S
Lehar
Sophie
S
Gillard
Geoffrey
G
Beers
Courtney
C
Dooley
James
J
Rubin
Jeffrey S
JS
Rudensky
Alexander
A
Farr
Andrew G
AG
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000096:biosynthesis / Q000235:genetics; D017637:Clonal Deletion; D003546:Cysteine Endopeptidases; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology; D051526:Fibroblast Growth Factor 10; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008247:Lysosomes / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins; D009924:Organ Culture Techniques; D051497:Receptor, Fibroblast Growth Factor, Type 2; D017468:Receptors, Fibroblast Growth Factor / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000196:embryology; D000094632:Thymic Stromal Lymphopoietin
D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D004268:DNA-Binding Proteins; C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D051526:Fibroblast Growth Factor 10; D000949:Histocompatibility Antigens Class II; D015850:Interleukin-6; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; C064655:V(D)J recombination activating protein 2; C045084:invariant chain; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors; D051497:Receptor, Fibroblast Growth Factor, Type 2; C065104:keratinocyte growth factor receptor; D002403:Cathepsins; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D000094632:Thymic Stromal Lymphopoietin