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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.

Original publication

DOI

10.1002/stem.2464

Type

Journal article

Journal

Stem cells (Dayton, Ohio)

Publication Date

12/2016

Volume

34

Pages

2902 - 2915

Addresses

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

Keywords

Thymus Gland, T-Lymphocytes, Bone Marrow Cells, Hematopoietic Stem Cells, Animals, Mice, Inbred C57BL, Sepsis, Atrophy, Lipopolysaccharides, Receptors, Chemokine, Poly I-C, Lymphocyte Count, Gene Expression Profiling, Hematopoiesis, Extramedullary, Lymphopoiesis, Myelopoiesis, Cell Proliferation, Cell Lineage, Male, Toll-Like Receptors