Fibrotic liver microenvironment promotes Dll4 and SDF-1-dependent T-cell lineage development.
Cell Death Dis
; 10(6): 440, 2019 06 05.
Article
em En
| MEDLINE
| ID: mdl-31165736
ABSTRACT
The reconstitution of the T-cell repertoire and quantity is a major challenge in the clinical management of HIV infection/AIDS, cancer, and aging-associated diseases. We previously showed that autologous bone marrow transfusion (BMT) via the hepatic portal vein could effectively restore CD4+ T-cell count in AIDS patients also suffering from decompensated liver cirrhosis. In the current study, we characterized T-cell reconstitution in a mouse model of liver fibrosis induced by CCl4 and found that T-cell reconstitution after BMT via hepatic portal vein was also greatly enhanced. The expression of Dll4 (Delta-like 4), which plays an important role in T-cell progenitor expansion, was elevated in hepatocytes of fibrotic livers when compared to normal livers. This upregulation of Dll4 expression was found to be induced by TNFα in an NFκB-dependent manner. Liver fibroblasts transfected with Dll4 (LF-Dll4) also gained the capacity to promote T-cell lineage development from hematopoietic stem cells (HSCs), resulting in the generation of DN2 (CD4 and CD8 DN 2) and DN3 T-cell progenitors in vitro, which underwent a normal maturation program when adoptively transferred into Rag-2 deficient hosts. We also demonstrated a pivotal role of SDF-1 produced by primary liver fibroblasts (primary LF) in T-lineage differentiation from HSCs. These results suggest that Dll4 and SDF-1 in fibrotic liver microenvironment could promote extrathymic T-cell lineage development. These results expand our knowledge of T-cell development and reconstitution under pathological conditions.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação ao Cálcio
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Células-Tronco Hematopoéticas
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Linfócitos T
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Diferenciação Celular
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Proteínas Adaptadoras de Transdução de Sinal
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Quimiocina CXCL12
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Cirrose Hepática
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China