Retinoic acid signaling in thymic epithelial cells regulates thymopoiesis

Despite the essential role of thymic epithelial cells (TEC) in T cell development, the signals regulating TEC differentiation and homeostasis remain incompletely understood. Here, we show a key in vivo role for the Vitamin A metabolite, retinoic acid (RA), in TEC homeostasis. In the absence of RA signaling in TEC, cortical TEC (cTEC) and CD80lo MHCIIlo medullary TEC (mTEC) displayed subset-specific alterations in gene expression, which in cTEC included genes involved in epithelial proliferation, development and differentiation. Mice whose TEC were unable to respond to RA showed increased cTEC proliferation, an accumulation of Sca1+ cTEC and, in early life, a decrease in mTEC numbers. These alterations resulted in reduced thymic cellularity in early life, a reduction in CD4SP and CD8SP numbers in both young and adult mice, and enhanced peripheral CD8+ T cell survival upon TCR stimulation. Collectively, our results identify RA as a regulator of TEC homeostasis that is essential for TEC function and normal thymopoiesis.