A unique and coordinated developmental program where fetal SI T cells shape ISC programming by balancing growth and differentiation is reported, offering a new therapeutic angle for intestinal diseases where these processes are disrupted.
Abstract
Although early-life immunity was once considered immature, the human fetal immune system is dynamic and compartmentalized by the 2nd trimester. By the 21st gestational week, T lymphocytes dominate the fetal small intestine (SI), yet their mucosal functions prenatally are unclear. Because fetal T cell infiltration is concomitant with rapid intestinal epithelial growth and differentiation in utero, we hypothesized that early-life intestinal T cells support normal mucosal development and function.
We generated an ex vivo co-culture model where SI T cells from fetal or adult donors are integrated with SI organoids, assessing organoid generation and differentiation by microscopy, single-cell RNA sequencing, and multiplexed cytokine assays. To complement our ex vivo approach, we also performed spatial transcriptomics on healthy and diseased SI tissue to investigate T cell-epithelial interactions throughout the human lifespan.
Fetal SI T cells significantly promoted organoid generation and cell cycling gene programs, even in organoids derived from adults or diseased neonates, suggesting they can reprogram the epithelium towards a regenerative state. Uniquely, fetal SI T cells also directed intestinal stem cell (ISC) differentiation towards the secretory lineage. Yet, adult SI T cells did not support organoid growth or differentiation, highlighting specialized roles of fetal T cells. To test whether secreted factors direct ISC fate, we cultured organoids with T cell-derived conditioned media, which was insufficient to stimulate organoid generation. Additionally, fetal SI T cells were significantly more likely to localize near ISCs, supporting the need for physical interactions.
Overall, we report a unique and coordinated developmental program where fetal SI T cells shape ISC programming by balancing growth and differentiation, offering a new therapeutic angle for intestinal diseases where these processes are disrupted.
NIH AI171980, AI179570; NIH P30DK034854-36; YSM Science Fellows 2024 Program and Grant; Yale Department of Pediatrics Trainee Pilot Grant
Mucosal and Regional Immunology (MUC)
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.
Michela Frascoli, Alyssa Berthelette, Joonsoo Kang et al.· Journal of Immunology· 0 citations
Type 1 and type 3 γδ T cells develop in the embryonic thymus, yet it is not known whether they continue to differentiate after birth in tissues. Here, we show that in the first week of life, intestinal γδ T cells up-regulated many T cell activation and type 3 genes, while the postweaning period was dominated by induction of genes related to effector function, type 1 immunity, and cytotoxicity. During this period, γδ T cells protected the gut from fungal infection. In the adult intestine, type 3 interleukin-17–producing γδ T cells (γδT17 cells) had a distinct phenotype, a Tbet-dependent type 1 immune profile and enhanced T cell receptor (TCR) signaling. Last, we found a γδT17 cell–like population in the neonatal human gut. Collectively, our data suggest that γδ T cells continue to mature after they leave the thymus and, upon localization to the gut, a dynamic temporal differentiation program reshapes type 3 cells into Tbet+ type 1 effectors with heightened TCR activity.
M. V. Baglioni, M. G. F. Fares da Silva, Andrea Sonnenholzner et al.· Science Advances· 0 citations
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.
D. Obwegs, Alexander Oschwald, L. Koetter et al.· Science Advances· 0 citations
Single-cell technologies have transformed our view of normal and malignant hematopoiesis, yet a framework linking lifelong homeostatic hematopoiesis to hematological diseases in blood ecosystem remains incomplete. Here, we constructed a high-resolution landscape of the entire hematopoietic system by integrating transcriptomes of ∼1 million cells from 207 healthy samples spanning five developmental stages (fetal, neonatal, childhood, adult, elderly), and identified 96 blood cell clusters, including a VNN2-marked monocyte subset in the fetus and TSHZ2-marked T cell subsets exhibiting distinct age-dependent dynamics. We uncovered a reversal in hematopoietic stem cell/multipotent progenitor (HSC/MPP) stemness around childhood and a postnatal lymphoid bias shift from reduced early B/T lineage potential to enhanced natural killer (NK) cytotoxicity, coordinately orchestrated by intracellular transcription factor activity and intercellular interactions. Projecting 116 pan-malignancy samples (9 hematological malignancies) to our refined blood cell reference, we identified the upregulation of MYC and MHC II signaling as relatively conserved features correlating with poor prognosis, while hematopoiesis-related modules exhibited subtype-specific distributions with divergent clinical implications. Importantly, we developed a prognostic framework incorporating two core signatures shared across hematological malignancies and subtype-specific features. We further revealed an antagonism between inflammatory and cytotoxic programs across malignancies. Together, we established a panoramic landscape of the human hematopoietic system and elaborated its lifelong behaviors, in which a steady-state reference enabled the delineation of pathological hallmarks across hematological malignancies.
Xiao-Wei Xie, Lian-Shuo Li, Fang Hong et al.· Protein & Cell· 0 citations
The gut microbiota is essential for immune system maturation in early life. The introduction of solid food at weaning triggers a transient immune response, the weaning reaction, which protects against colitis and colorectal cancer later in life. However, the impact of dietary-induced microbial dysbiosis during weaning on long-term intestinal homeostasis remains unclear. We aimed to determine whether and how microbial dysbiosis during weaning affects mucosal homeostasis and susceptibility to colitis and colorectal cancer in adulthood.
Mice were fed diets differing in fiber quantities during weaning. After weaning, offspring were maintained on standard chow. Microbiota composition, and intestinal immune cell populations were studied. Adult susceptibility was evaluated using DSS-induced colitis, AOM/DSS-induced colitis-associated cancer, and spontaneous intestinal cancer (ApcMin/+) models. To study the contribution of T cells, scRNA-seq was performed on CD4-positive T cells, and transgenic mice were used to track specific, transient CD4+ T cell subsets. Bulk RNA-seq of the colon and T cell transfer experiments were also conducted. The causal role of early-life microbiota was tested by transferring microbiota into germ-free mice.
Early-life dietary variation induced subtle changes in microbiota, reflected in shifts in immune cell populations at weaning. These early differences were associated with altered adult responses to colitis and colorectal cancer, indicating lasting effects on mucosal homeostasis. Specific CD4+ T cell subsets were modulated by early-life microbiota, and colon transcriptomics revealed persistent changes. Microbiota transfer into germ-free neonates demonstrated that early-life microbial communities alone were sufficient to shape long-term intestinal outcomes, highlighting a critical window during weaning for immune programming.
Microbial composition during weaning plays a central role in establishing long-term mucosal homeostasis.
This project supported by the European Research Council Starting Grant, Swiss National Science Foundation, Helmut Horten Stiftung, Swiss Cancer Research Foundation, Kenneth Rainin Foundation, Inselspital, Ruth & Arthur Scherbarth Stiftung, Novartis Founda
Mucosal and Regional Immunology (MUC)
Z. Al Nabhani, Luis Morelli· Journal of Immunology· 0 citations
The relationship between lineage output and transcriptional features of hematopoietic stem cells (HSCs) has been reported in adult bone marrow, yet it remains unclear in fetal liver, given their distinct developmental stage and microenvironment. Here, we systematically characterized the functions of E14.5 mouse fetal liver HSCs by lentiviral barcode labeling followed by transplantation, with subsequent single-cell RNA sequencing (scRNA-seq) and clonal analysis performed on donor-derived HSCs and their progeny in recipient bone marrow. We identified three HSC subtypes based on lineage bias, with myeloid-biased and balanced subtypes predominating. Importantly, within the same subtype, HSCs and their progeny share several transcriptional programs, and these programs show minimal overlap between subtypes. We term the retention of subtype-specific transcriptional features across lineages as "transcriptional persistence". Notably, this phenomenon was not observed in adult bone marrow. Alternatively, classification by progeny output activity revealed the presence of low-output and high-output subtypes within fetal liver HSCs. Although these two subtypes showed no significant difference in stemness features, they exhibited distinct transcriptional features and signaling activation states, which also differed from their counterparts in bone marrow, indicating that the biological characteristics of HSCs with different output activities vary by developmental stage. Of note, in both fetal liver and adult bone marrow, transcriptional persistence showed no obvious correlation with output activity, suggesting a specific coupling relationship between transcriptional persistence and lineage bias. Collectively, our study provides a clonal-resolution view of fetal liver HSC heterogeneity, enhancing our understanding of HSC diversity across different developmental stages.
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