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 Cxcl12, Dll4, and Psmbll 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 Cxcl12l~(DsRed) reporter mouse model, we show that changes in Cxcll2 expression reveal a developmentally regulated program of cTEC heterogeneity. Although cTECs are uniformly Cxcl12~(DsRed+) during neonatal stages, progression through postnatal life triggers the appearance of Cxcl12~(DsRed-) cTECs that continue to reside in the cortex alongside their Cxcl12~(DsRed+) counterparts. This appearance of Cxcl12~(DsRed-)- 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 Cxcl12~(DsRed+) and Cxcl12~(DsRed-) cTECs share a common Foxn1~+ cell origin, RNA sequencing analysis shows Cxcl12~(DsRed-) cTECs no longer express Foxnl, which results in loss of the FOXN1-dependent cTEC gene signature and may explain the reduced capacity of Cxcl12~(DsRed-) 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 Foxn1 expression and its key target genes, which may then determine the functional competence of the thymic cortex.
展开▼
