Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice

Abstract

Fetal growth restriction (FGR) causes a wide variety of defects in the neonate which can lead to increased risk of heart disease, diabetes, anxiety and other disorders later in life. However, the effect of FGR on the immune system, is poorly understood. We used a well-characterized mouse model of FGR in which placental Igf-2 production is lost due to deletion of the placental specific Igf-2 P0 promotor. The thymi in such animals were reduced in mass with a ~70% reduction in cellularity. We used single cell RNA sequencing (Drop-Seq) to analyze 7,264 thymus cells collected at postnatal day 6. We identified considerable heterogeneity among the Cd8/Cd4 double positive cells with one subcluster showing marked upregulation of transcripts encoding a sub-set of proteins that contribute to the surface of the ribosome. The cells from the FGR animals were underrepresented in this cluster. Furthermore, the distribution of cells from the FGR animals was skewed with a higher proportion of immature double negative cells and fewer mature T-cells. Cell cycle regulator transcripts also varied across clusters. The T-cell deficit in FGR mice persisted into adulthood, even when body and organ weights approached normal levels due to catch-up growth. This finding complements the altered immunity found in growth restricted human infants. This reduction in T-cellularity may have implications for adult immunity, adding to the list of adult conditions in which the in utero environment is a contributory factor.

Thymic Epithelial Cell-Derived IL-15 and IL-15 Receptor α Chain Foster Local Environment for Type 1 Innate Like T Cell Development

“…Recently, murine TECs have been defined into 5 subsets based on single cell RNA sequencing analysis (42)(43)(44)(45)(46)(47)(48). To further investigate expression of cytokines and their receptors in TEC subsets, we analyzed scRNAseq data of TECs generated by the Ido Amit group, which had sequenced more TECs than other reports (42).…”

Transcriptome profiling of human thymic CD4+ and CD8+ T cells compared to primary peripheral T cells

“…A high-dimensional atlas of human T cell diversity in eight different tissues has been reported, using CyTOF [10], but neither thymus nor peripheral blood from children was among those tissues. In mice, single-cell transcriptomic atlases of the developing [11] and neonatal murine thymus [12] was recently released, providing detailed insights of the development of thymocytes into mature T cells. Previously, transcriptome profiling using microarray of flow sorted cells from murine thymi has been reported, including for CD4+ and CD8+ T cells [13,14].…”

Transcriptome profiling of human thymic CD4+ and CD8+ T cells compared to primary peripheral T cells

“…A high-dimensional atlas of human T cell diversity in eight different tissues has been reported, using CyTOF (10), but neither thymus nor peripheral blood from children was among those tissues. In mice, single-cell transcriptomic atlases of the developing (11) and neonatal murine thymus (12) was recently released, providing detailed insights of the development of thymocytes into mature T cells.…”