| First Author | Gülich AF | Year | 2019 |
| Journal | Front Immunol | Volume | 10 |
| Pages | 409 | PubMed ID | 30915074 |
| Mgi Jnum | J:284329 | Mgi Id | MGI:6380848 |
| Doi | 10.3389/fimmu.2019.00409 | Citation | Gulich AF, et al. (2019) Differential Requirement of Cd8 Enhancers E8I and E8VI in Cytotoxic Lineage T Cells and in Intestinal Intraepithelial Lymphocytes. Front Immunol 10:409 |
| abstractText | CD8 expression in T lymphocytes is tightly regulated by the activity of at least six Cd8 enhancers (E8I-E8VI), however their complex developmental stage-, subset-, and lineage-specific interplays are incompletely understood. Here we analyzed ATAC-seq data on the Immunological Genome Project database and identified a similar developmental regulation of chromatin accessibility of a subregion of E8I, designated E8I-core, and of E8VI. Loss of E8I-core led to a similar reduction in CD8 expression in naive CD8(+) T cells and in IELs as observed in E8 I (-/-) mice, demonstrating that we identified the core enhancer region of E8I. While E8 VI (-/-) mice displayed a mild reduction in CD8 expression levels on CD8SP thymocytes and peripheral CD8(+) T cells, CD8 levels were further reduced upon combined deletion of E8I-core and E8VI. Moreover, activated E8 I -core(-/-) E8 VI (-/-) CD8(+) T cells lost CD8 expression to a greater degree than E8 I -core(-/-) and E8 VI (-/-) CD8(+) T cells, suggesting that the combined activity of both enhancers is required for establishment and maintenance of CD8 expression before and after TCR activation. Finally, we observed a severe reduction of CD4 CTLs among the TCRbeta(+)CD4(+) IEL population in E8 I -core(-/-) but not E8 VI (-/-) mice. Such a reduction was not observed in Cd8a (-/-) mice, indicating that E8I-core controls the generation of CD4 CTLs independently of its role in Cd8a gene regulation. Further, the combined deletion of E8I-core and E8VI restored CD4 CTL subsets, suggesting an antagonistic function of E8VI in the generation of CD4 CTLs. Together, our study demonstrates a complex utilization and interplay of E8I-core and E8VI in regulating CD8 expression in cytotoxic lineage T cells and in IELs. Moreover, we revealed a novel E8I-mediated regulatory mechanism controlling the generation of intestinal CD4 CTLs. |
