Lamprey <i>FOXN1</i> rescues the block of thymic epithelial cell development in the mouse <i>Foxn1</i> -deficient thymic rudiment

All vertebrate adaptive immune systems exhibit distinct lymphocyte lineages. In jawless vertebrates, such as lampreys, T-like cells are thought to develop in lympho-epithelial structures at the tips of gill filaments, termed thymoids. However, it is unclear whether thymoids are functionally equivalent to the thymus of jawed vertebrates. Indeed, because the structural modules that are somatically assembled to form the antigen receptors of jawless and jawed vertebrates differ, development and selection of T cells may be governed by clade-specific genetic networks. To address this question, we have replaced the mouse <i>Foxn1</i> gene, a key regulator of the thymic microenvironment in jawed vertebrates, with the orthologous <i>FOXN1</i> lamprey gene, which is expressed in the thymoids alongside genes orthologous to known targets of the mouse Foxn1 transcription factor. The reconstituted thymi support normal T cell development, and, to a lesser extent, also support B cell development, indicating that the lamprey <i>FOXN1</i> gene can rescue the block of thymic epithelial cell differentiation in mice deficient for the endogenous <i>Foxn1</i> gene. The absence of overt autoimmunity in transgenic mice suggests that the reconstituted thymic microenvironment directs the development of a self-tolerant T cell repertoire. These findings highlight the remarkable similarity of thymic epithelial functions in jawed and jawless vertebrates, despite more than 500 My of independent evolution. Our results thus suggest that the emergence of the Foxn1 transcription factor in the common ancestor of vertebrates was associated with the advent of a specialized tissue environment supporting the development and selection of T cells.