Thymic epithelial cells (TECs) provide the basic architecture for the development of thymocytes. TEC is regenerative after impairment in thymus of young mice. However, how this regeneration program is governed remains unclear. Transcription factor Foxn1 is a central mediator of the differentiation and function of TEC. We examined the relation between thymic injury and Foxn1 in TEC. Total body irradiation (TBI) treatments induced up-regulation of Foxn1 in TEC, which was abolished when thymic function recovered. Specific depletion of double positive (DP) thymocytes triggered the up-regulation of Foxn1. On the other hand, extracellular IL-22 is a potential regulator of homeostasis of TEC. We demonstrated that TBI treatments also induced the up-regulation of intrathymic IL-22. Expression pattern of Foxn1 shares similar characteristics with IL-22. Furthermore, Foxn1 related genes that regulate the function of TEC were also up-regulated. Thus, our data reveal that TBI treatment triggers regeneration program of TEC.