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

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.

Administration of RANKL boosts thymic regeneration upon bone marrow transplantation

“…Consistently, we found that LTα expression is required for the expression of adhesion molecules and chemokines, known to promote T‐cell progenitor entry in the thymus, in stromal cells during BMT. In accordance with our data, it has been recently reported that LTβR regulates at steady state thymus homing by controlling VCAM‐1 and ICAM‐1 on endothelial cells (Lucas et al , ; Shi et al , ). Peripheral T‐cell reconstitution is thus altered in BM‐transplanted LTα −/− mice, which is explained by a diminished thymic export of CD4 + and CD8 + T cells revealed by a weak frequency of recent thymic emigrants.…”

Endothelial cells act as gatekeepers for LTβR-dependent thymocyte emigration

“…Given the widespread LTβR expression by multiple thymic stromal cell types ( Fig. 2 A ; Shi et al, 2016 ; Sitnik et al, 2016 ; Cosway et al, 2017 ), any cell type–specific requirements for LTβR during thymus emigration are unknown. To address this, we generated mice lacking LTβR in specific stromal cells.…”

“…3 I ), suggesting LTβR controls egress independently of these molecules. Finally, a novel LTβR-dependent Ly6C − CD62P + thymic endothelial subset termed the portal endothelium has been recently identified and linked to regulation of lymphoid progenitor cell entry ( Shi et al, 2016 ). In agreement with these studies, we observed significant loss of Ly6C − CD62P + portal endothelium in LTβR ENDO mice ( Fig.…”

Chemokine-Mediated Choreography of Thymocyte Development and Selection

“…P-selectin expression is upregulated on EC when TSP cellularity diminishes[17], suggesting a positive feedback loop through which EC recruit TSP as space becomes available. Thymic EC are heterogeneous, and both KitL + EC[18] and P-selectin + Ly6c lo EC[19,20] have been implicated as TSP portals. However, these two candidates differ in expression of genes critical for differentiation of immature thymocytes, such as Cxcl12 and Dll4, leaving open the question of which serves as the true TSP niche.…”