Submitted October 1, 2007
Accepted March 28, 2008
TGF-
signaling in thymic epithelial cells regulates thymic involution and post-irradiation reconstitution
Mathias M Hauri-Hohl, Saulius Zuklys, Marcel P Keller, Lukas T Jeker, Thomas Barthlott, Anne M Moon, Jurgen Roes, and Georg A Hollander*
Department of Clinical-Biological Sciences, Pediatric Immunology and The Children's University Hospital, Basel, Switzerland
Division of Pediatric Critical Care, Utah Health Sciences Center, Salt Lake City, Utah, United States
Department of Immunology and Molecular Pathology, University College London, London, United Kingdom
* Corresponding author; email: georg-a.hollaender{at}unibas.ch.
The thymus constitutes the primary lymphoid organ responsible for the generation of naive T cells. Its stromal compartment is largely composed of a scaffold of different subsets of epithelial cells that provide soluble and membrane-bound molecules essential for thymocyte maturation and selection. With senescence, a steady decline in the thymic output of T cells has been observed. Numeric and qualitative changes in the stromal compartment of the thymus resulting in reduced thymopoietic capacity have been suggested to account for this physiological process. The precise cellular and molecular mechanisms underlying thymic senescence are, however, only incompletely understood. Here, we demonstrate that TGF-
signaling in thymic epithelial cells exerts a direct influence on the cell's capacity to support thymopoiesis in the aged mouse as the physiological process of thymic senescence is mitigated in mice deficient for the expression of TGF-RII on thymic epithelial cells. Moreover, TGF- signaling in these stromal cells transiently hinders the early phase of thymic reconstitution following myeloablative conditioning and hematopoietic stem cell transplantation. Hence, inhibition of TGF- signaling decelerates the process of age-related thymic involution and may hasten the reconstitution of regular thymopoiesis following hematopoietic stem cell transplantation.
