The cortical thymic epithelial cell compartment is shaped by stage-specific thymocyte crosstalk which drives loss of Foxn1 and its key target genes

ABSTRACT: In the thymus, cortical and medullary thymic epithelial cells (TEC) support the production of abT-cells from bone marrow-derived progenitors. For cortical TEC (cTEC), the expression a specialised gene signature that encodes multiple key regulators including CXCL12, Delta-like 4 (DLL4) and b5t enables the cortex to support T-lineage commitment, and the generation and selection of CD4+CD8+ thymocytes. While the importance of the cTEC in T-cell development are well defined, the mechanisms that shape the cTEC compartment and maintain its functional specialisation are unclear. Using CXCL12DsRed reporter mice, we show that changes in expression of the chemokine CXCL12 reveal a developmentally regulated programme of cTEC heterogeneity. While cTEC uniformly express CXCL12 during neonatal stages, progression through postnatal life triggers the appearance of CXCL12- cTEC subset that continues to reside in the cortex. We show the appearance of CXCL12- cTEC is influenced by the maturation of CD4-CD8-, but not CD4+CD8+ thymocytes, demonstrating stage-specific thymocyte crosstalk controls cTEC heterogeneity. Importantly, while fate mapping experiments show that both CXCL12+ and cTEC12- cTEC arise from cells expressing Foxn1, RNA sequencing analysis shows they are genetically distinct. Thus, CXCL12- cTEC lack Foxn1 expression, which directs loss of the Foxn1-dependent cTEC gene signature that may explain the reduced capacity of CXCL12- cTEC for thymocyte interactions. In sum, our study shows that shaping of cTEC compartment during the life-course occurs via stage-specific thymocyte crosstalk which drives loss of Foxn1 and its key target genes, that may then determine the functional competence of the thymic cortex.

ORGANISM(S): Mus musculus

PROVIDER: GSE205940 | GEO | 2022/10/28

REPOSITORIES: GEO