Sepsis-Induced Thymic Atrophy Is Associated with Defects in Early Lymphopoiesis

Author:

Kong Yaxian12,Li Yajie12,Zhang Weimei12,Yuan Shaoxin12,Winkler René3,Kröhnert Ulrike3,Han Junyan12,Lin Tao12,Zhou Yu4,Miao Peng5,Wang Beibei12,Zhang Jianping12,Yu Zhengya5,Zhang Yu4,Kosan Christian3,Zeng Hui12

Affiliation:

1. Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China

2. Beijing Key Laboratory of Emerging Infectious Diseases, Beijing, China

3. Department of Biochemistry, Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University, Jena, Germany

4. Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology (Ministry of Health), Peking University Health Science Center, Beijing, China

5. Department of Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China

Abstract

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.

Funder

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

Reference73 articles.

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