Fibrotic liver microenvironment promotes Dll4 and SDF-1-dependent T-cell lineage development

Zheng Gong,Yunpeng Chu,Yongjing Chen,Qing Li,Yin Huang,Ying Wang,Keli Liu,Baochi Liu,Changshun Shao,Luo-Wei Wang ,Chenchang Xu,Rui Li ,Yanyan Han,Xiao Chen ,Qianwen Shang,Xiaoren Zhang,Bingxue Shang,Yanan Li,Zhiyuan Zheng,Shiu‐Ru Lin ,Yufang Shi

doi:10.1038/s41419-019-1630-1

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.

Highlights

Introduction Reconstitution ofT cells is a major clinical challenge in patients suffering from HIV/AIDS, cancer, and agingassociated diseases
We previously showed that administration of autologous bone marrow transfusion (BMT) via the hepatic portal vein could effectively restore CD4+ T-cell count in AIDS patients who were suffering from decompensated liver cirrhosis[8,9]
We here showed that mice with liver fibrosis exhibit greater T-lineage reconstitution after irradiation and BMT by the hepatic portal vein, which recapitulates the clinical observations in AIDS patients with liver cirrhosis who received autologous BMT via hepatic portal vein

Summary

Introduction

Introduction Reconstitution ofT cells is a major clinical challenge in patients suffering from HIV/AIDS, cancer, and agingassociated diseases. We previously showed that administration of autologous bone marrow transfusion (BMT) via the hepatic portal vein could effectively restore CD4+ T-cell count in AIDS patients who were suffering from decompensated liver cirrhosis[8,9]. This observation indicates a possibility that the cirrhotic liver microenvironment may possess lymphopoiesis supportive activity that can direct autologous hematopoietic stem/ progenitor cells to undergo differentiation toward early T lineage. CD4+CD8+ DP thymocytes are subjected to positive and negative selection in the thymus[12] Following these selections, mature, CD4 or CD8 SP thymocytes are exported from the thymus to establish the pool of self-restricted and functional T cells in the periphery[13]

Methods

Results

Conclusion