Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells.
The systemic administration of keratinocyte growth factor (KGF) enhances T-cell lymphopoiesis in normal mice and mice that received a bone marrow transplant. KGF exerts protection to thymic stromal cells from cytoablative conditioning and graft-versus-host disease-induced injury. However, little is known regarding KGF's molecular and cellular mechanisms of action on thymic stromal cells. Here, we report that KGF induces in vivo a transient expansion of both mature and immature thymic epithelial cells (TECs) and promotes the differentiation of the latter type of cells. The increased TEC numbers return within 2 weeks to normal values and the microenvironment displays a normal architectural organization. Stromal changes initiate an expansion of immature thymocytes and permit regular T-cell development at an increased rate and for an extended period of time. KGF signaling in TECs activates both the p53 and NF-kappaB pathways and results in the transcription of several target genes necessary for TEC function and T-cell development, including bone morphogenetic protein 2 (BMP2), BMP4, Wnt5b, and Wnt10b. Signaling via the canonical BMP pathway is critical for the KGF effects. Taken together, these data provide new insights into the mechanism(s) of action of exogenous KGF on TEC function and thymopoiesis.
Rossi
Simona W
SW
Laboratory of Pediatric Immunology, Center for Biomedicine, Department of Clinical-Biological Sciences, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
Jeker
Lukas T
LT
Ueno
Tomoo
T
Kuse
Sachiyo
S
Keller
Marcel P
MP
Zuklys
Saulius
S
Gudkov
Andrei V
AV
Takahama
Yousuke
Y
Krenger
Werner
W
Blazar
Bruce R
BR
Holländer
Georg A
GA
D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000276:immunology* / Q000494:pharmacology; D038041:Lymphopoiesis / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000276:immunology
D019485:Bone Morphogenetic Proteins; C496454:Fgf7 protein, mouse; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D051523:Fibroblast Growth Factor 7