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distinct output potentials for na\u00efve 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 na\u00efve 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 counterparts, indicating the enhanced stability. Together, our work reveals that the neonatal-TD Treg are more immunosuppressive, which is likely shaped primarily by environmental factors.<\/jats:p>","DOI":"10.1093\/jmcb\/mjac072","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T16:41:20Z","timestamp":1671554480000},"source":"Crossref","is-referenced-by-count":8,"title":["scRNA-seq profiling of neonatal and adult thymus-derived CD4+ T cells by a T cell origin-time tracing model"],"prefix":"10.1093","volume":"14","author":[{"given":"Yuheng","family":"Han","sequence":"first","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxing","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"},{"name":"Department of Tumor Biology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200030 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Chen","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujing","family":"Lai","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongxiang","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningbo","family":"Wu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Ruan","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limin","family":"Lu","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Su","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"},{"name":"Center for Human Translational Immunology at Shanghai Institute of Immunology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"},{"name":"Shanghai Jiao Tong University School of Medicine\u2013Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine , Shanghai 200025 , China"},{"name":"Key Laboratory of Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University , Changsha 410008 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,12,20]]},"reference":[{"key":"2023052608120139800_bib1","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nri1394","article-title":"Neonatal adaptive immunity comes of age","volume":"4","author":"Adkins","year":"2004","journal-title":"Nat. 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