Biology subjects

Yin, Y. S.

Publications and source records attributed to Yin, Y. S..

5 recordsLinked to original sources

bioRxiv2026

Weaning imprints a hybrid cytotoxic-regulatory identity on intestinal CD4+ T lymphocytes

The intestinal immune system must adapt as the neonatal gut shifts from milk to solid food and becomes densely colonized. How the T cell compartment is established under these conditions remains unclear. Using fate-mapping to timestamp naive T cells, with imaging, transcriptomic, and repertoire analyses, we tracked them from suckling to adulthood. Intestinal T cell entry peaked at weaning, coinciding with relocation from crypts to villi guided by the tissue microenvironment and, partly, the microbiota. T cells timestamped at suckling persisted into adulthood and, at weaning, adopted a transient cytotoxic-regulatory state in the lamina propria, with granzyme B expression microbiota-dependent only in the ileum. Clonal expansions at weaning were restricted to the small intestinal lamina propria and absent in germ-free mice. Most expanded clones recognized early-life commensals. Weaning is a physiological window of transient inflammation imprinting a hybrid CD4 T cell compartment, suggesting that early-life commensals modulate T cell selection.

immunology↗

bioRxiv2026

Urea is a dynamic and functional component of mammalian breast milk

Urea is a constituent of human milk, yet its regulation and interactions with the infant gut microbiome remain unclear. Combining three human cohorts, a controlled mouse model, and complementary microbiome analyses, we show that milk urea increases across lactation, is conserved across mammals, and is not explained by circulating urea levels or maternal diet. Instead, we identify lactation-dependent remodeling of mammary urea-metabolism and transport pathways, including dynamic AQP3 localization in secretory epithelium, indicative of regulated transfer of circulating urea into breast milk. Alongside urea, maternal milk and stool provide complementary reservoirs of urea-metabolizing bacteria that help establish the infant "ureabiome", whose urea-utilization capacity is supported by metagenomics. This maternal-infant axis is context-dependent: infant formulas provide substantially higher urea levels than human milk, while functional assays show that urea supports both commensal and opportunistic bacteria in a concentration-dependent manner. Together, these findings define a maternal nitrogen axis through which lactation can shape the assembly and function of the infant gut microbiome.

microbiology↗

bioRxiv2026

Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses

Colorectal cancer (CRC) remains a leading cause of cancer mortality, with most cases refractory to immunotherapy. Distinguishing tumor-induced from steady-state mucosal T cell responses has been a critical barrier to understanding antitumor immunity in CRC. Using orthotopic transplantation of CRC organoids with and without metastatic potential, combined with temporal T cell fate-mapping, we show that non-metastatic tumors elicit early recruitment of CD8{beta} and CD4 T cells that acquired cytotoxic and Th1-like programs, whereas pro-metastatic tumors induce a naive-like, hypoactivated state. Tumor-infiltrating CD4+ T cells underwent clonal expansion, including clones recognizing microbial and dietary antigens. T cells in physical contact with tumor cells, identified by uLIPSTIC, were enriched for expanded and cytotoxic clones. Fate-mapped T cells from non-metastatic tumors suppressed tumor growth in an IFN-{gamma}-dependent manner, whereas pro-metastatic tumor-derived T cells failed to do so. Mechanistically, pro-metastatic tumors downregulated MHCII, and Ciita targeting in non-metastatic organoids reduced CD4 clonal expansion and led to tumor progression. Together, these findings define divergent early T cell trajectories associated with CRC metastatic potential, indicating that ineffective local immune engagement precedes metastatic dissemination.

immunology↗

bioRxiv2025

Gut microbiota phospholipids regulate intestinal gene expression and can counteract the effects of antibiotic treatment

The gut microbiome influences immune and metabolic homeostasis. Our research using non-obese diabetic (NOD) mice revealed that early-life antibiotic exposure remodels the gut microbiome affecting metabolism and accelerating type 1 diabetes (T1D) incidence, with cecal material transplant (CMT) mitigating the damage. Now examining murine intestinal lipidomic profiles, we identified 747 compounds. Comparing the lipidomic profiles of cecal contents of conventional and germ-free mice and their diets, we identified 87 microbially-produced lipids reduced by antibiotic exposure but CMT-restored. Parallel analysis of human fecal lipid profiles after azithromycin-exposure showed significant alterations with substantial overlap with mice. In vitro co-culture with mouse macrophages or small intestinal epithelial cells and human colonic epithelial cells identified phospholipids that repress inflammation through the NF{kappa}B pathway. Oral administration of these phospholipids to antibiotic-treated NOD mice reduced expression of ileal genes involved in early stages of T1D pathogenesis. These findings indicate potential therapeutic anti-inflammatory roles of microbially-produced lipids.

microbiology↗

bioRxiv2023

Antiviral innate immune memory in alveolar macrophages following SARS-CoV-2 infection.

Pathogen encounter results in long-lasting epigenetic imprinting that shapes diseases caused by heterologous pathogens. The breadth of this innate immune memory is of particular interest in the context of respiratory pathogens with increased pandemic potential and wide-ranging impact on global health. Here, we investigated epigenetic imprinting across cell lineages in a disease relevant murine model of SARS-CoV-2 recovery. Past SARS-CoV-2 infection resulted in increased chromatin accessibility of type I interferon (IFN-I) related transcription factors in airway-resident macrophages. Mechanistically, establishment of this innate immune memory required viral pattern recognition and canonical IFN-I signaling and augmented secondary antiviral responses. Past SARS-CoV-2 infection ameliorated disease caused by the heterologous respiratory pathogen influenza A virus. Insights into innate immune memory and how it affects subsequent infections with heterologous pathogens to influence disease pathology could facilitate the development of broadly effective therapeutic strategies.

immunology↗