Age-related thymic involution is associated with loss of medullary epithelial subsets and regulated by Foxn1 (86.1)

Abstract

Abstract Age-related thymic involution results from deterioration of the interaction between hematopoietic progenitors and non-hematopoietic thymic epithelial cells (TECs). The involution may be primarily triggered by deterioration of TECs. Therefore we focus on the role of TEC-autonomous gene Foxn1, which is largely undefined in postnatal thymic function and aging. We generated a conditional Foxn1 knockout mouse (fx). Through a tamoxifen-inducible ubiquitous Cre (uCreERT), a postnatal deletion of Foxn1 caused dramatically acute thymic involution within 5 days. The involution was associated with more impairment in medullary TECs (mTECs) than in cortical TECs, especially MHC-IIhiUEA-1hi and K5+ mTECs. The phenotypes were very similar to the naturally aged murine thymus, in which the MHC-IIhiUEA-1hi mTEC subset had a decrease correlated with age, and coincided with reported results showing that the K5+ mTECs were reduced in the naturally aged thymus (Gui. J. Int. Immuno. 07). A more physiologically relevant progressive loss of Foxn1 via a low level of spontaneous activation of the uCreERT transgene in CreERT-fx/fx and CreERT-fx/+ mice caused the similar effects, including acceleration of thymic involution, reduced K5+ mTECs and MHC-IIhiUEA-1hi mature mTECs with age, beginning at 3 months of age, which is much earlier than that in fx/fx and wild type mice. Combining with previous report that naturally aged mice have gradually reduced Foxn1 mRNA expression, we believe that Foxn1 is involved in age-related thymic involution through impairment of specific epithelial cell subpopulations. It causes deterioration of the postnatal thymic microenvironment, thereby triggers the thymic involution. (Partially supported by grants from NIAID/NIH to DMS).