Differential Requirement of Cd8 Enhancers E8I and E8VI in Cytotoxic Lineage T Cells and in Intestinal Intraepithelial Lymphocytes
| Autor: | Gülich, Alexandra Franziska, Preglej, Teresa, Hamminger, Patricia, Alteneder, Marlis, Tizian, Caroline, Orola, Maria Jonah, Muroi, Sawako, Taniuchi, Ichiro, Ellmeier, Wilfried, Sakaguchi, Shinya |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
CD8 Antigens cytotoxic T cells Immunology T cell development CD4 CTLs Mice Transgenic CD8 transgenic/knockout mice Mice Inbred C57BL Mice Gene Expression Regulation IELs Animals enhancer Intestinal Mucosa gene regulation lcsh:RC581-607 Intraepithelial Lymphocytes Original Research T-Lymphocytes Cytotoxic |
| Zdroj: | Frontiers in Immunology, Vol 10 (2019) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| DOI: | 10.3389/fimmu.2019.00409/full |
| Popis: | 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 naïve CD8+ T cells and in IELs as observed in E8I−/− mice, demonstrating that we identified the core enhancer region of E8I. While E8VI−/− 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 E8I-core−/−E8VI−/− CD8+ T cells lost CD8 expression to a greater degree than E8I-core−/− and E8VI−/− 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 TCRβ+CD4+ IEL population in E8I-core−/− but not E8VI−/− 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. |
| Databáze: | OpenAIRE |
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