Diversity in Cortical Thymic Epithelial Cells Occurs through Loss of a Foxn1-Dependent Gene Signature Driven by Stage-Specific Thymocyte Cross-Talk

In the thymus, cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells support αβT cell development from lymphoid progenitors. For cTECs, expression of a specialized gene signature that includes , , and enables the cortex to support T lineage commitment and the generation and selection of CD4 CD8 thymocytes. Although the importance of cTECs in T cell development is well defined, mechanisms that shape the cTEC compartment and regulate its functional specialization are unclear. Using a reporter mouse model, we show that changes in expression reveal a developmentally regulated program of cTEC heterogeneity. Although cTECs are uniformly during neonatal stages, progression through postnatal life triggers the appearance of cTECs that continue to reside in the cortex alongside their counterparts. This appearance of cTECs is controlled by maturation of CD4 CD8 , but not CD4 CD8 , thymocytes, demonstrating that stage-specific thymocyte cross-talk controls cTEC heterogeneity. Importantly, although fate-mapping experiments show both and cTECs share a common cell origin, RNA sequencing analysis shows cTECs no longer express , which results in loss of the FOXN1-dependent cTEC gene signature and may explain the reduced capacity of cTECs for thymocyte interactions. In summary, our study shows that shaping of the cTEC compartment during the life course occurs via stage-specific thymocyte cross-talk, which drives loss of expression and its key target genes, which may then determine the functional competence of the thymic cortex.