Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells

Abstract

Thymic epithelial cell differentiation, growth and function depend on the expression of the transcription factor Foxn1, however its target genes have never been physically identified. Using novel static and inducible genetic model systems and chromatin studies, we provide now a genome wide map of direct Foxn1 target genes for postnatal thymic epithelia and define the Foxn1 binding motif. We detail the function of Foxn1 in these cells and demonstrate that in addition to the transcriptional control of genes involved in the attraction and lineage commitment of T cell precursors, Foxn1 regulates the expression of genes involved in antigen processing and thymocyte selection. Thus, critical events in thymic lympho-stromal cross-talk and T cell selection are indispensably choreographed by Foxn1.

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

“…Furthermore, there is increasing evidence that FOXN1 is also important during thymic regeneration, as forced induction of FOXN1 is capable of reversing age-related thymic atrophy (18, 19) and recombinant FOXN1 protein can enhance T cell reconstitution after HCT (45). However, despite its importance for thymic function, it was only recently in a series of elegant studies by Hollander and colleagues that a comprehensive list of 450 high-confidence direct targets of FOXN1 were identified in cTECs (21). Importantly, this list of targets verified the four putative FOXN1 targets ( Dll4, Kitl, Ccl25 , and Cxcl12 ) that had been previously identified (20, 42).…”

Acute Thymic Involution and Mechanisms for Recovery

“…Inactivation of the retinoblastoma protein (RB) family enhances thymic function and prevents ATI by controlling forkhead-box transcription factor n1 (Foxn1) expression (Garfin et al 2013). Foxn1 controls the differentiation of TECs and regulates the expression of genes implicated in the selection of thymocytes (Zuklys et al 2016). Palifermin (rhKGF) can target the RB-E2F genes in murine TECs and the RB-E2F-Foxn1 module, and thus controls the size and function of the thymus and plays a key role in thymic regeneration (Garfin et al 2014).…”

FOXN1 Deficiency: from the Discovery to Novel Therapeutic Approaches

“…2). In a Foxn1-dependent manner, TECs release several chemokines, including CCL25, CCL21, and CXCL12, that allow hematopoietic progenitors to enter into the developing thymus [33,34]. These progenitors, subsequently, are committed to a T cell fate and progress through the different phases of the ontogenesis, thanks to the crosstalk with TECs and under the stimuli of TEC-derived molecules, such as the notch ligand DLL4, which, in turn, is also transcriptionally regulated by FOXN1 [35,36].…”

“…In addition to CCL25, CXCL12, and DLL4, FOXN1 has been recently proven to promote the expression of hundreds of genes in TECs that support intrathymic T cell development through the antigen processing and presentation. In particular, it was found that the expression of Prss16 in cTECs, which encodes a thymusspecific serine protease required for CD4 lineage selection and high MHCII expression, is regulated by Foxn1 [34]. Moreover, a direct binding target of Foxn1 has been detected uniquely in cTECs, represented by a cis-regulatory element involved in the transcriptional promotion of relevant cTEC genes.…”

“…Indeed, the Foxn1 binding to this element promotes the transcription of β5t gene, the catalytic subunit of cTEC thymoproteasome, which has an essential role in positive selection induction of functionally competent CD8 + T cells within the thymus [40]. In the absence of FOXN1 expression in TECs, the thymic development is thereby blocked at a rudimentary stage [27,28,34], characterized by an alymphoid two-dimensional anlage with a cystic structure [22,41,42]. In this thymic rudiment, TECs are not capable to allow the hematopoietic precursor cells (HPCs) to enter into the epithelial cluster [43].…”