RANK Signaling in the Differentiation and Regeneration of Thymic Epithelial Cells.

Magali Irla

doi:10.3389/fimmu.2020.623265

Abstract

Thymic epithelial cells (TECs) provide essential clues for the proliferation, survival, migration, and differentiation of thymocytes. Recent advances in mouse and human have revealed that TECs constitute a highly heterogeneous cell population with distinct functional properties. Importantly, TECs are sensitive to thymic damages engendered by myeloablative conditioning regimen used for bone marrow transplantation. These detrimental effects on TECs delay de novo T-cell production, which can increase the risk of morbidity and mortality in many patients. Alike that TECs guide the development of thymocytes, reciprocally thymocytes control the differentiation and organization of TECs. These bidirectional interactions are referred to as thymic crosstalk. The tumor necrosis factor receptor superfamily (TNFRSF) member, receptor activator of nuclear factor kappa-B (RANK) and its cognate ligand RANKL have emerged as key players of the crosstalk between TECs and thymocytes. RANKL, mainly provided by positively selected CD4+ thymocytes and a subset of group 3 innate lymphoid cells, controls mTEC proliferation/differentiation and TEC regeneration. In this review, I discuss recent advances that have unraveled the high heterogeneity of TECs and the implication of the RANK-RANKL signaling axis in TEC differentiation and regeneration. Targeting this cell-signaling pathway opens novel therapeutic perspectives to recover TEC function and T-cell production.

Highlights

The thymus supports the generation of distinct T-cell subsets such as conventional CD4+ and CD8+ T cells, Foxp3+ regulatory T cells, gd T cells, and invariant natural killer T cells
They express CXCL12 and CCL25 chemokines that guide the homing of T-cell progenitors into the thymus [5, 6]. cortical TECs (cTECs) express the NOTCH ligand Delta-like 4 (DLL4), which induces the engagement of progenitors into the T-cell lineage [7, 8]
Compared to cTECs, medullary TECs (mTECs) are better characterized, likely because they are more abundant. mTECs have the unique ability to express up to 85%–90% of the genome and virtually all protein-coding genes [18]. This promiscuous gene expression program is induced by the autoimmune regulator (Aire) and the transcription factor Fez family zinc finger 2 (Fezf2) [18, 19]. mTECs contain two main subsets identified on MHCII and CD80 cell surface expression levels: MHCIIloCD80lo and MHCIIhiCD80hi [20]

Summary

Magali Irla*

Aix Marseille Univ, CNRS, INSERM, CIML, Centre d’Immunologie de Marseille-Luminy, Marseille, France. TECs are sensitive to thymic damages engendered by myeloablative conditioning regimen used for bone marrow transplantation. These detrimental effects on TECs delay de novo T-cell production, which can increase the risk of morbidity and mortality in many patients. I discuss recent advances that have unraveled the high heterogeneity of TECs and the implication of the RANK-RANKL signaling axis in TEC differentiation and regeneration. Targeting this cell-signaling pathway opens novel therapeutic perspectives to recover TEC function and T-cell production

INTRODUCTION

TEC HETEROGENEITY IN MOUSE AND HUMAN

FEATURES OF MEDULLARY TECs

AND DIFFERENTIATION

Findings

SENSIBILITY OF TECs TO MYELOABLATIVE CONDITIONING REGIMEN