The role of Klf4 in thymic epithelial cells

Abstract

Abstract Thymic epithelial cells (TECs) are essential for the development and the selection of naïve T cells that will be able to discriminate the non-self from self-peptides. The thymus is the organ that starts degenerating the earliest in the organism, leading to a decrease in naïve T cell production. Starting from 1 year old in humans, thymic involution accelerates at puberty, partially caused by an increase in circulating sex steroids (SS). SS induce thymic involution, mediated indirectly by nuclear receptors in TECs. Little is known about how and why the age-related thymic involution is induced. We identified Klf4 as a potential regulator of TEC function and differentiation. Klf4 is a transcription factor that induces differentiation and inhibits proliferation in epithelial cells from various tissues. We showed that Klf4 expression is negatively correlated with TEC proliferation in different contexts. Interestingly, Klf4 is known as a mediator of nuclear receptors response and is a sex hormone target in several tissues. We discovered that Klf4 was more expressed in male TECs than in female TECs. Importantly, TECs are less proliferative in males than in females. Moreover, Klf4 expression was reduced when males were castrated. These results suggest that Klf4 has an important role in TEC homeostasis and is a mediator of SS response. We are currently testing the role of Klf4 in TECs by phenotypic and transcriptomic analysis on transgenic mice in which Klf4 is specifically deleted in TECs. Using testosterone treatment, we are studying the effect of SS on TEC and thymic output with or without Klf4 expression. Finally, we will assess the direct KLF4 target genes in TECs using ChIP-Seq.