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  Stat3 in Thymic Epithelial Cells Is Essential for Postnatal Maintenance of Thymic Architecture and Thymocyte Survival



The crosstalk between thymocytes and thymic epithelial cells (TEC) is required not only for thymocyte differentiation, but also for TEC maturation to build up thymic architecture. Although the mechanism underlying thymocyte differentiation has been appreciably elucidated, the molecular events for TEC differentiation or signaling events required for the crosstalk remained unclear. To investigate the role of Stat3 in TEC, we established mice with TEC-specific deletion of Stat3 by taking advantage of the Cre-loxP system behind the keratin 5 promoter, which is active in TEC, but not in thymocytes. Thymi of the newborn mutant mice appeared normal in terms of size, population of thymocytes and TEC morphology. However, when they reached to adolescence, the size of thymi became smaller than those of control mice. As they became older, their thymi underwent severe atrophy (Figure A, control vs KO) accompanied by decrease of thymocyte number, morphological changes in TEC and destruction of thymic architecture. TUNEL stain (Red in Figure B) of old thymi revealed that, compared with control mice, Stat3-deficient mice harbored a lot of apoptotic thymocytes whereas TEC (genetically-marked with GFP) were negative for TUNEL. Even before adolescence, the thymocytes of Stat3-deficient mice were highly sensitive to suboptimal doses of glucocorticoid, or γ-irradiation in vivo, although thier thymocytes themselves did not show increased sensitivity in vitro. Together, these results suggest that deletion of Stat3 in TEC sensitizes thymocytes to either spontenous or inductive apoptosis. Analysis of differential gene expression between control and the mutant TEC revealed that Stat3 deficiency resulted in overexpression of ErbB2 and H-2Oβ, a nonclassical class II molecule, both of which could be downstream molecules that Stat3 of TEC normally represses their expression in order to protect thymocytes from environmental apoptotic stimuli, including aging.


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