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Blood, 1 May 2007, Vol. 109, No. 9, pp. 3803-3811.
Prepublished online as a Blood First Edition Paper on January 9, 2007; DOI 10.1182/blood-2006-10-049767.
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IMMUNOBIOLOGY
Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells
Simona W. Rossi1,
Lukas T. Jeker1,
Tomoo Ueno2,
Sachiyo Kuse2,
Marcel P. Keller1,
Saulius Zuklys1,
Andrei V. Gudkov3,
Yousuke Takahama2,
Werner Krenger1,
Bruce R. Blazar4, and
Georg A. Holländer1
1 Laboratory of Pediatric Immunology, Center for Biomedicine, Department of Clinical-Biological Sciences, University of Basel and The University Children's Hospital (UKBB), Basel, Switzerland;
2 Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima, Japan;
3 Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH;
4 University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN
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- B 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.
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