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scRNA-seq profiling of neonatal and adult thymus-derived cD4+ T cells by a T cell origin-time tracing model

Journal of Molecular cell Biology 2022年第12期14卷 1-16页

作者： yuheng Han Xinxing Ouyang yao chen Shujing Lai Hongxiang Sun Ningbo Wu chun Ruan Limin Lu Bing Su shanghai Institute of Immunology Department of Immunology and Microbiologyand the Ministry of Education Key Laboratory of Cell Death and DifferentiationShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Tumor Biology Shanghai Chest HospitalShanghai Jiao Tong University School of MedicineShanghai 200030China center for Human Translational Immunology at shanghai Institute of Immunology Ruijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China shanghai Jiao Tong University School of Medicine–yale Institute for Immune Metabolism Shanghai Jiao Tong University School of MedicineShanghai 200025China Key Laboratory of Molecular Radiation Oncology of Hunan Province Xiangya HospitalCentral South UniversityChangsha 410008China

It is well documented that the neonatal thymus-derived (neonatal-TD) regulatory T cells (Treg) are essential to prevent lethal autoimmune diseases and allergies, and neonatal and adult thymus possesses distinct output potentials for naïve T cells, including Treg. However, the molecular features and detailed functional differences between neonatal-TD and adult thymus-derived (adult-TD) T cells in terms of their ability to maintain immune homeostasis during long-term environmental influences are still largely unknown, partially due to the lack of appropriate animal models to precisely trace these cells at specific time points. In this study, neonatal-TD and adult-TD cD4+ T cells from the spleen and Peyer's patches were traced for 9 weeks by a T cell origin-time tracing mouse model and analysed by single-cell RNA sequencing. More Treg but fewer naïve T cells were found in neonatal-TD cD4+ T cells from both tissues than those from adult-TD counterparts. Interestingly, the neonatal-TD Treg in both the spleen and Peyer's patches exhibited augmented expression of Foxp3, Gata3, ctla4, Icos, Il2ra, Tgfb1, and Nrp1, as well as enriched Gene Ontology terms like T cell activation and tolerance induction, indicating an enhanced immunosuppressive function. These results were further confirmed by flow cytometry analysis and in vitro immune suppression assays. Flow cytometry also revealed a significantly higher proportion of neonatal-TD Treg in total Treg than that of adult-TD counterparts, suggesting the longer lifespan of neonatal-TD Treg. To investigate the intrinsic features of neonatal-TD and adult-TD cD4+ T cells, a shortened tracing time was performed. Surprisingly, the neonatal-TD and adult-TD cD4+ T cells had similar proportions of Treg and did not exhibit significant differences in Foxp3, Gata3, ctla4, Icos, Il2ra, and Tgfb1 expression levels after tracing for 12 days. On the other hand, neonatal-TD Treg present an increased Nrp1 expression level compared with adult-TD co

关键词： T lineage tracing Treg neonatal thymus-derived T cells neonatal thymus-derived Treg single-cell RNA sequencing

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