Ly6d expression delineates two putative postnatal thymus epithelial progenitor cells that are differentially affected by aging

Distinct postnatal trajectories of mouse dendritic epidermal T cells and Langerhans cells independent of microbiota

The mouse epidermis harbors two key resident immune populations—dendritic epidermal T cells (DETCs), a subset of invariant γδ T cells, and Langerhans cells (LCs), specialized tissue-resident macrophages—both of which play critical roles in immune surveillance, barrier integrity, and tissue homeostasis. While their fetal origin has been defined, the mechanisms governing their postnatal maturation remain poorly understood. Here, we present a combined immunophenotypic and single-cell transcriptomic map of DETC and LC development from late embryogenesis through adulthood in mice. We delineate distinct differentiation trajectories characterized by dynamic changes in morphology, proliferation, and transcriptional programming. Using γδ T cell deficient mice, we show that LC maturation proceeds independently of canonical γδDETCs, likely due to compensatory αβDETCs. Analysis of germfree mice and wildlings further demonstrates that the postnatal DETC and LC differentiation is independent of microbial colonization. Comparative analysis with developing human epidermis reveals partially conserved differentiation programs. Together, our findings define core principles underlying establishment of the epidermal immune niche.

Differentiated thymic epithelial cells adopt gene-expression and micro-environmental niches unique to the thymus 2310220

The thymus contains a multitude of epithelial cell types that work in concert to educate immature T cells called thymocytes to distinguish self from non-self. A subset of thymic epithelial cells (TECs) express lineage defining transcription factors and differentiate into cell types -- such as muscle, neuroendocrine, and tuft cells -- that are typically found in peripheral tissues. However, the function and organization of these differentiated TECs especially in the human thymus are poorly understood. Specifically, much remains unknown about the gene regulation that enable their function, and their structural morphology and spatial localization in the thymus to ultimately orchestrate thymocyte education. To resolve the diversity of TECs at a single cell resolution, we simultaneously profiled the gene expression and chromatin accessibility of human thymus samples. We integrated our data with all available thymic single cell datasets to establish concordant cell annotations across studies. We leveraged the CELLxGENE database to identify unique gene signatures in the differentiated thymic TECs compared to their peripheral counterparts in 31 tissues. Informed by the gene expression of maturing thymic muscle cells, we used quantitative microscopy to evaluate their cellular morphology and spatial localization in the thymus. We show that differentiated TECs share substantial celltype restricted genes, yet take on a celltype specific identity, a phenomenon not shared by their peripheral counterparts. Narrowing in on the maturation of thymic muscle cells, we show that they have distinct cellular morphologies and thymic spatial localization as they differentiate. Differentiated thymic celltypes, while sharing similarity to their peripheral counterparts, take on a thymus specific identity. Furthermore, thymic muscle cells have distinct cell morphology and micro-environmental niche as they mature. NIH Computational and Systems Immunology (COMP)

In-Utero Imprinting of Gene Regulatory Networks Underpinning Innate-Like T Cell Development 2260347

Using mice carrying a mutation in the CBFβ2 isoform, it is demonstrated that CBFβ2 haploinsufficiency rewires transcriptional regulatory circuits in adult bone marrow progenitors, rendering them permissive for an early life-restricted Tγδ17 cells.

Prdm15 deficiency perturbs hematopoietic stem and progenitor cell homeostasis.

It is reported that Prdm15 deficiency in HSPCs induces the accumulation of immature hematopoietic stem cells in mice, establishing PRDM15 as a critical epigenetic regulator of HSPCs, offering valuable insights into the molecular mechanisms underlying hematopoietic homeostasis.

Neogenin-1 marks myeloid-primed fetal hematopoietic stem cells that undergo progressive lineage-restriction with age

Spatial remodeling of the thymic stroma with age disrupts niches for T cell selection and tolerance

Age-associated thymic involution is a major driver of immunosenescence, yet the cellular and spatial mechanisms coordinating age-related thymic remodeling remain incompletely understood. Combining single-cell transcriptomics, chromatin accessibility profiling, and spatial transcriptomics, we generated a spatially resolved multi-omic atlas of the aging mouse thymus. We show that thymic aging is not simply a process of epithelial loss, but a spatial reorganization of the stroma into new microenvironments, including age-associated epithelial states, a fibroblast-supported epithelial progenitor niche, and tertiary lymphoid structures. This remodeling displaces niches supporting positive and negative thymocyte selection and coincides with an intrinsic decline in cortical thymic epithelial cell function. Ligand-receptor mapping identifies medullary fibroblasts as a signaling hub sustaining epithelial progenitors and promoting tertiary lymphoid structure neogenesis, linking these hallmarks of thymic aging. Together, our findings reframe thymic involution as spatial stromal reorganization that links stromal remodeling to impaired thymopoiesis, central tolerance, and immune aging.