Abstract
T cell ontogeny is a sophisticated process, which takes place within the thymus through a series of well-defined discrete stages. The process requires a proper lympho-stromal interaction. In particular, cortical and medullary thymic epithelial cells (cTECs, mTECs) drive T cell differentiation, education, and selection processes, while the thymocyte-dependent signals allow thymic epithelial cells (TECs) to maturate and provide an appropriate thymic microenvironment. Alterations in genes implicated in thymus organogenesis, including Tbx1, Pax1, Pax3, Pax9, Hoxa3, Eya1, and Six1, affect this well-orchestrated process, leading to disruption of thymic architecture. Of note, in both human and mice, the primordial TECs are yet unable to fully support T cell development and only after the transcriptional activation of the Forkhead-box n1 (FOXN1) gene in the thymic epithelium this essential function is acquired. FOXN1 is a master regulator in the TEC lineage specification in that it down-stream promotes transcription of genes, which, in turn, regulate TECs differentiation. In particular, FOXN1 mainly regulates TEC patterning in the fetal stage and TEC homeostasis in the post-natal thymus. An inborn null mutation in FOXN1 leads to Nude/severe combined immunodeficiency (SCID) phenotype in mouse, rat, and humans. In Foxn1−/− nude animals, initial formation of the primordial organ is arrested and the primordium is not colonized by hematopoietic precursors, causing a severe primary T cell immunodeficiency. In humans, the Nude/SCID phenotype is characterized by congenital alopecia of the scalp, eyebrows, and eyelashes, nail dystrophy, and a severe T cell immunodeficiency, inherited as an autosomal recessive disorder. Aim of this review is to summarize all the scientific information so far available to better characterize the pivotal role of the master regulator FOXN1 transcription factor in the TEC lineage specifications and functionality.
Highlights
The thymus is the primary lymphoid organ with the unique function to produce and to maintain the pool of mature and functional T cells
These data suggest that adult thymic epithelial cells (TECs) maintain the receptivity to cross talk with thymocytes despite a prolonged absence of T cell precursors. The absence of both thymocytes and of the 3D framework may result in changes of the keratin genes expression, inducing the cortical thymic epithelial cells (cTECs) and medullary TECs (mTECs) to undergo a de-differentiation process and to reacquire the precursor K5+K8+ cellular phenotype. These findings suggest that signals from early CD4–CD8– DN T cell precursors and/or their immediate progeny provide necessary signals to promote the formation of the thymic cortex, while, later in ontogeny, the differentiation of TECs into a medullary phenotype are clearly dependent on the presence of CD4+CD8− and CD4−CD8+ single positive (SP) thymocytes [21,22,23]
Since Forkhead-box n1 (FOXN1) is selectively expressed in the thymus and skin, one possibility to explain the presence of the few non-functional CD8+TCRγδ+ cells in Nude/severe combined immunodeficiency (SCID) fetus is that skin epithelial cells could play a partial role in T cell ontogeny, as already shown in in vitro models [138, 139]
Summary
The thymus is the primary lymphoid organ with the unique function to produce and to maintain the pool of mature and functional T cells. The expression of Forkhead-box transcription factor n1 (Foxn1) approximately at E11.5 is crucial for the subsequent epithelial differentiation, since in its absence, the colonization of the anlage by T cell progenitors from the bone marrow fails [62] and the subsequent T cell development and TECs formation is aborted, resulting in a severe immunodeficiency [63, 64, 66, 154].
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