| First Author | White AJ | Year | 2022 |
| Journal | J Immunol | PubMed ID | 36375838 |
| Mgi Jnum | J:353737 | Mgi Id | MGI:7444899 |
| Doi | 10.4049/jimmunol.2200609 | Citation | White AJ, et al. (2022) Diversity in Cortical Thymic Epithelial Cells Occurs through Loss of a Foxn1-Dependent Gene Signature Driven by Stage-Specific Thymocyte Cross-Talk. J Immunol |
| abstractText | In the thymus, cortical thymic epithelial cells (cTECs) and medullary thymic epithelial cells support alphabetaT cell development from lymphoid progenitors. For cTECs, expression of a specialized gene signature that includes Cxcl12, Dll4, and Psmb11 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 Cxcl12 (DsRed) reporter mouse model, we show that changes in Cxcl12 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 Foxn1, 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. |
