Maintenance of a normal thymic microenvironment and T-cell homeostasis require Smad4-mediated signaling in thymic epithelial cells.
Signals mediated by the transforming growth factor-beta superfamily of growth factors have been implicated in thymic epithelial cell (TEC) differentiation, homeostasis, and function, but a direct reliance on these signals has not been established. Here we demonstrate that a block in canonical transforming growth factor-beta signaling by the loss of Smad4 expression in TECs leads to qualitative changes in TEC function and a progressively disorganized thymic microenvironment. Moreover, the number of thymus resident early T-lineage progenitors is severely reduced in the absence of Smad4 expression in TECs and directly correlates with extensive thymic and peripheral lymphopenia. Our observations hence place Smad4 within the signaling events in TECs that determine total thymus cellularity by controlling the number of early T-lineage progenitors.
Jeker
Lukas T
LT
Department of Biomedicine, Laboratory of Pediatric Immunology, University of Basel and the University Children's Hospital, Basel, Switzerland.
Barthlott
Thomas
T
Keller
Marcel P
MP
Zuklys
Saulius
S
Hauri-Hohl
Mathias
M
Deng
Chu-Xia
CX
Holländer
Georg A
GA
D000818:Animals; D001483:Base Sequence; D018925:Chemokines / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011247:Pregnancy; D015398:Signal Transduction; D051901:Smad4 Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic
D018925:Chemokines; D018076:DNA, Complementary; D051901:Smad4 Protein; C490810:Smad4 protein, mouse