title: Sepsis-Induced Thymic Atrophy Is Associated with Defects in Early Lymphopoiesis.
abstract: Impaired T lymphopoiesis is associated with immunosuppression of the adaptive immune response and plays a role in the morbidity and mortality of patients and animal models of sepsis. Although previous studies examined several intrathymic mechanisms that negatively affect T lymphopoiesis, the extrathymic mechanisms remain poorly understood. Here, we report a dramatic decrease in the percentage of early T lineage progenitors (ETPs) in three models of sepsis in mice (cecal ligation and puncture, lipopolysaccharide continuous injection, and poly I:C continuous injection). However, septic mice did not show a decrease in the number of bone marrow (BM) precursor cells. Instead, the BM progenitors for ETPs expressed reduced mRNA levels of CC chemokine receptor (CCR) 7, CCR9 and P-selectin glycoprotein ligand 1, and exhibited impaired homing capacity in vitro and in vivo. Furthermore, RNA-Seq analysis and real-time PCR showed a marked downregulation of several lymphoid-related genes in hematopoietic stem and progenitor cells. Hematopoietic stem and progenitor cells differentiated into myeloid cells but failed to generate T lymphocytes in vitro and in vivo. Our results indicate that the depletion of ETPs in septic mice might be a consequence of an impaired migration of BM progenitors to the thymus, as well as a defect in lymphoid lineage commitment. Stem Cells 2016;34:2902-2915.
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Yaxian
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Weimei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Shaoxin
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Biochemistry, Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University, Jena, Germany.
authors.forename: René
authors.initials: R
authors.lastname: Winkler
authors.affiliation: Department of Biochemistry, Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University, Jena, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kröhnert
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Junyan
authors.initials: J
authors.lastname: Han
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Lin
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology (Ministry of Health), Peking University Health Science Center, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Miao
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
authors.forename: Zhengya
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology (Ministry of Health), Peking University Health Science Center, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University, Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kosan
authors.affiliation: Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zeng
mesh_terms: D000818:Animals; D001284:Atrophy; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D006411:Hematopoiesis, Extramedullary / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D018655:Lymphocyte Count; D038041:Lymphopoiesis / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D038042:Myelopoiesis / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000378:metabolism; D018805:Sepsis / Q000150:complications* / Q000235:genetics / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology*; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D019707:Receptors, Chemokine; D051193:Toll-Like Receptors; D011070:Poly I-C
keywords: Emergency hematopoiesis; Hematopoietic stem cells; Lineage commitment; Sepsis; T lymphopoiesis; Thymic atrophy