Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the life span
Gray, Joshua I, et al.
Sci Immunol,2024
The unique γδ T cell subset expressing the γδ T cell receptor are implicated in immune responses to tumors and certain pathogens. However, the understanding of the functional role of human γδ T cells in tissues is very limited. In this paper, the authors present a comprehensive analysis of human γδ T cells in blood and mucosal and lymphoid tissues of organ and living blood donors across the life span. They found that γδ T cells are enriched in tissues during childhood. They further explored the differences between γδ1 and γδ2 cells. γδ1 cells were the predominant subset in spleens, jejuna, and mesenteric LNs (MLNs) in children, and decreased in lymphoid organs with growth. In adults, γδ2 cells predominate in blood, whereas γδ1 cells are enriched across tissues and express residency profiles. In the blood, spleens, and lungs, γδ1 cells acquired a terminally differentiated effector (TEMRA) phenotype, whereas γδ2 cells acquired TEM phenotypes in the blood and MLNs. Also, their scRNA-seq data showed that pediatric tissue γδ T cells exhibit features of postthymic differentiation. Adult γδ T cells scRNA-seq data also suggested heterogeneous subtypes in different tissue. They then directly compared transcriptional profiles of pediatric and adult γδ T cells. γδ T cells in children contained naïve and tissue-adapted subtypes that were essentially missing from the adult dataset. Compared with adults, effector γδ1 cells in children were enriched for genes associated with TCR-mediated activation and cell-cycle regulation. They further examined the differences in functional capacity between pediatric and adult tissue γδ T cells. It’s suggested that functional capacities of γδ T cells are subset-, site-, and age-dependent. They concluded that tissue γδ T cells undergo dynamic maturation with age, resulting in disseminated, clonally expanded cytolytic subsets that may function in immunosurveillance.DOI: 10.1126/sciimmunol.adn3954
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Direct observation of a condensate effect on super-enhancer controlled gene burstingManyu Du, et al.
Cell, 2024
Super-enhancers (SEs), clusters of enhancers that are occupied by exceptionally high densities of transcriptional machinery, regulate genes with especially important roles in cell identity. It’s reported that diffraction-sized condensates exited on RNA polymerase II (RNA Pol II) but their function in gene expression regulation remained unclear. In this paper, the authors developed live-cell super-resolution and multi-color 3D-imaging approaches to investigate putative roles of endogenous condensates in the regulation of super-enhancer controlled gene Sox2. Firstly, they fuse RPB1, the largest subunit of RNA Pol II) with a green-to-red photoconvertible protein Dendra2 and generated the cell line enabling dual-color live-cell and super-resolution imaging of RNA Pol II molecules as well as visualizing the Sox2 gene locus. They observed an increase in burst size with proximal clusters and higher bursting frequency for proximal clusters. Then they deleted two proximal DNase I hypersensitive sites on Sox2 to reduce its expression by CRISPR. They found that that the CTCF-binding sites and proximal “weak” enhancer regions are important for the condensate’s proximal burst enhancement. Next, they characterized the long-term diffusional dynamics of RNA Pol II condensates and Sox2 gene locus using lattice light sheet imaging in live stem cells. They observed that there was a direct anti-correlation between burst intensity and the condensate-to-gene distance. What’s more, they performed three-color lattice light sheet imaging to monitor the locations and intensities of Sox2 control region (SCR), condensate (Mediator or RNA Pol II), and Sox2 mRNA in real time. In conclusion, they propose a three-way kissing model whereby the condensate interacts transiently with gene locus and regulatory DNA elements to control gene bursting.DOI: 10.1016/j.cell.2023.12.005Editor & Reviewer: Congci Yu
