title: Timely and spatially regulated maturation of B and T cell repertoire during human fetal development.
abstract: Insights into the ontogeny of the human fetal adaptive immune system are of great value for understanding immunocompetence of the developing fetus. However, to date, this has remained largely uncharted territory, in large part because blood samples from healthy, early gestation fetuses have been hard to come by. In a comprehensive study, we analyzed levels of T cell receptor excision circles (TRECs), signal-joint κ receptor excision circles (sjKRECs), and intron recombination signal sequence-K-deleting element (iRSS-Kde) rearrangement, and T and B lymphocyte repertoire clonality in human fetuses from 12 to 26 weeks of gestational age. Using next-generation sequencing, we analyzed the diversity and complexity of T cell receptor β (TRB) and immunoglobulin heavy chain (IGH) repertoires in four fetuses at 12, 13, 22, and 26 weeks of gestation and in healthy full-term infants. We report the progressive increase of TREC, sjKREC, and iRSS-Kde levels over time and confirm that B cell development precedes T cell development in the human fetus. Temporally and spatially regulated maturation of B and T cell repertoire diversity and complexity during human fetal development was observed, including evidence that immunoglobulin somatic hypermutation and class switch recombination occur already during intrauterine life. Our results help define physiological levels of immunodeficiency in premature infants and may serve as a reference for future studies aimed at investigating the impact of intrauterine pathologies on fetal immune development and function.
authors.affiliation: Pediatric Immunology Unit, Jeffrey Modell Foundation Center, and Department of Pediatrics, the Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 5262100, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Rechavi
authors.affiliation: Pediatric Immunology Unit, Jeffrey Modell Foundation Center, and Department of Pediatrics, the Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 5262100, Israel.
authors.forename: Atar
authors.initials: A
authors.lastname: Lev
authors.affiliation: Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA 02459, USA.
authors.forename: Yu Nee
authors.initials: YN
authors.lastname: Lee
authors.affiliation: Pediatric Immunology Unit, Jeffrey Modell Foundation Center, and Department of Pediatrics, the Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 5262100, Israel. Hematology Laboratory, Cancer Research Center, Sheba Medical Center, Tel Hashomer 5262100, Israel.
authors.forename: Amos J
authors.initials: AJ
authors.lastname: Simon
authors.affiliation: Department of Obstetrics and Gynecology, Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 5262100, Israel.
authors.forename: Yoav
authors.initials: Y
authors.lastname: Yinon
authors.affiliation: Department of Obstetrics and Gynecology, Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 5262100, Israel.
authors.forename: Schlomo
authors.initials: S
authors.lastname: Lipitz
authors.affiliation: Hematology Laboratory, Cancer Research Center, Sheba Medical Center, Tel Hashomer 5262100, Israel.
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.affiliation: Department of Obstetrics and Gynecology, Talpiot Medical Leadership Program, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 5262100, Israel. boaz.weisz@sheba.health.gov.il luigi.notarangelo@childrens.harvard.edu raz.somech@sheba.health.gov.il.
authors.forename: Boaz
authors.initials: B
authors.lastname: Weisz
authors.affiliation: Division of Immunology, Children's Hospital, Harvard Medical School, Boston, MA 02459, USA. The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02459, USA. Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. boaz.weisz@sheba.health.gov.il luigi.notarangelo@childrens.harvard.edu raz.somech@sheba.health.gov.il.
authors.forename: Luigi D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Pediatric Immunology Unit, Jeffrey Modell Foundation Center, and Department of Pediatrics, the Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 5262100, Israel. boaz.weisz@sheba.health.gov.il luigi.notarangelo@childrens.harvard.edu raz.somech@sheba.health.gov.il.
authors.forename: Raz
authors.initials: R
authors.lastname: Somech
mesh_terms: D000906:Antibodies / Q000097:blood / Q000276:immunology; D000941:Antigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D022801:Complementarity Determining Regions / Q000276:immunology; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D047109:Fetal Development / Q000276:immunology*; D006801:Humans; D017578:Immunoglobulin Class Switching; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry; D007223:Infant; D011247:Pregnancy; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D027041:Somatic Hypermutation, Immunoglobulin; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000906:Antibodies; D000941:Antigens; D022801:Complementarity Determining Regions; D007143:Immunoglobulin Heavy Chains; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta