LTβR controls thymic portal endothelial cells for haematopoietic progenitor cell homing and T-cell regeneration.

Yaoyao Shi,Yang-Xin Fu,Hairong Xu,Mengjie Lv,Huan Xia,Yu Hou,Weiwei Wu,Caiwei Jin,Boyang Ren,Zhongnan Wang,Qingqing Li,Mingzhao Zhu,Qian Chai,Xiaohuan Guo

doi:10.1038/ncomms12369

Abstract

Continuous thymic homing of haematopoietic progenitor cells (HPCs) via the blood is critical for normal T-cell development. However, the nature and the differentiation programme of specialized thymic endothelial cells (ECs) controlling this process remain poorly understood. Here using conditional gene-deficient mice, we find that lymphotoxin beta receptor (LTβR) directly controls thymic ECs to guide HPC homing. Interestingly, T-cell deficiency or conditional ablation of T-cell-engaged LTβR signalling results in a defect in thymic HPC homing, suggesting the feedback regulation of thymic progenitor homing by thymic products. Furthermore, we identify and characterize a special thymic portal EC population with features that guide HPC homing. LTβR is essential for the differentiation and homeostasis of these thymic portal ECs. Finally, we show that LTβR is required for T-cell regeneration on irradiation-induced thymic injury. Together, these results uncover a cellular and molecular pathway that governs thymic EC differentiation for HPC homing.

Highlights

Continuous thymic homing of haematopoietic progenitor cells (HPCs) via the blood is critical for normal T-cell development
Thymic homing HPCs differentiate into early T-cell progenitors (ETPs), which undergo T-cell development and maturation
We have identified a critical role for the lymphotoxin beta receptor (LTbR) signalling pathway in the specialized differentiation of thymic endothelial cells (ECs) (TPECs) for HPC thymic homing and T-cell regeneration

Summary

Introduction

Continuous thymic homing of haematopoietic progenitor cells (HPCs) via the blood is critical for normal T-cell development. We show that LTbR is required for T-cell regeneration on irradiation-induced thymic injury Together, these results uncover a cellular and molecular pathway that governs thymic EC differentiation for HPC homing. Further understanding of the cellular and molecular mechanisms controlling thymic ECs may provide novel insight into thymic HPC homing, and T-cell development and regeneration. The lymphotoxin beta receptor (LTbR) signalling pathway, engaged by the ligands of lymphotoxin (LT) and/or LIGHT, plays a crucial role in the development and function of high ECs (HECs) for the lymph node (LN) homing of lymphocytes[17,18,19,20,21]. We uncovered an interesting cellular and molecular pathway whereby positively selected T cells, but not other cells, orchestrate thymic HPC homing in an LTbR-dependent manner via thymic ECs

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Results

Conclusion