Ets1 Promotes the Differentiation of Post-Selected iNKT Cells through Regulation of the Expression of Vα14Jα18 T Cell Receptor and PLZF.

Ya-Ting Chuang,Tzong-Shyuan Tai,Chih-Chun Liu,Wan-Chu Chuang,Huang-Yu Yang,I-Cheng Ho,Yu-Wen Huang,Chia-Wei Liu

doi:10.3390/ijms222212199

Abstract

The transcription factor Ets1 is essential for the development/differentiation of invariant Natural Killer T (iNKT) cells at multiple stages. However, its mechanisms of action and target genes in iNKT cells are still elusive. Here, we show that Ets1 is required for the optimal expression of the Vα14Jα18 T cell receptor (TCR) in post-selected thymic iNKT cells and their immediate differentiation. Ets1 is also critical for maintaining the peripheral homeostasis of iNKT cells, which is a role independent of the expression of the Vα14Jα18 TCR. Genome-wide transcriptomic analyses of post-selected iNKT cells further reveal that Ets1 controls leukocytes activation, proliferation differentiation, and leukocyte-mediated immunity. In addition, Ets1 regulates the expression of ICOS and PLZF in iNKT cells. More importantly, restoring the expression of PLZF and the Vα14Jα18 TCR partially rescues the differentiation of iNKT cells in the absence of Ets1. Taken together, our results establish a detailed molecular picture of how Ets1 regulates the stepwise differentiation of iNKT cells.

Highlights

Invariant Natural Killer T cells are a unique subset of T cells expressing an invariant TCRα chain (Vα14Jα18 in mouse and Vα24Jα18 in human) [1,2]
It has a broad and profound impact on the transcriptome of the development of invariant Natural Killer T (iNKT) cells and is essential for their differentiation beyond stage 0. Such a broad impact on the transcriptome very likely explains why its action cannot be fully recapitulated by the restoration of the Vα14Jα18 T cell receptor (TCR) and/or PLZF, which are two target genes of Ets1
The dependence on Ets1 for the expression of TCR appears to be unique to iNKT cells because the level of TCR in Ets1KO conventional T cells is normal [36]

Summary

Introduction

Invariant Natural Killer T (iNKT) cells are a unique subset of T cells expressing an invariant TCRα chain (Vα14Jα18 in mouse and Vα24Jα18 in human) [1,2]. These cells differentiate from double-positive (DP) thymocytes and are functionally defined by reactivity to α-galactosylceramide (αGC). Unlike conventional T cells, iNKT cells are selected by CD1d expressing DP thymocytes but not MHC of thymic epithelial cells [3,4]. Upon CD1d-mediated selection, according to the traditional lineage maturation model, immature iNKT cells (CD24hiNK1.1−CD44−, stage 0) differentiate into three sequential stages: CD24−NK1.1−CD44− (stage 1), CD24−NK1.1−CD44+ (stage 2), and CD24−NK1.1+CD44+ (stage 3) [5,6]. INKT1 cells belong to the stage 3 population, iNKT2 cells belong to the stage 1 and stage 2 populations, and iNKT17 cells belong to the stage 2 population [7]

Methods

Results

Conclusion