MicroRNA-155 Controls iNKT Cell Development and Lineage Differentiation by Coordinating Multiple Regulating Pathways.

Kai Li,Xilin Zhang,Stephen L Brown,Xiaojun Wu,Tingting Liu,Li Zhou,Jie Wang,Guihua Li,Qing-Sheng Mi

doi:10.3389/fcell.2020.619220

Kai Li, Xilin Zhang + Show 7 more

Open Access

https://doi.org/10.3389/fcell.2020.619220

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Abstract

The development of invariant natural killer T (iNKT) cells requires a well-attuned set of transcription factors, but how these factors are regulated and coordinated remains poorly understood. MicroRNA-155 (miR-155) is a key regulator of numerous cellular processes that affects cell development and homeostasis. Here, we found that miR-155 was highly expressed in early iNKT cells upon thymic selection, and then its expression is gradually downregulated during iNKT cell development. However, the mice with miR-155 germline deletion had normal iNKT cell development. To address if downregulated miR-155 is required for iNKT cell development, we made a CD4Cre.miR-155 knock-in (KI) mouse model with miR-155 conditional overexpression in the T cell lineage. Upregulated miR-155 led to interruption of iNKT cell development, diminished iNKT17 and iNKT1 cells, augmented iNKT2 cells, and these defects were cell intrinsic. Furthermore, defective iNKT cells in miR-155KI mice resulted in the secondary innate-like CD8 T cell development. Mechanistically, miR-155 modulated multiple targets and signaling pathways to fine tune iNKT cell development. MiR-155 modulated Jarid2, a critical component of a histone modification complex, and Tab2, the upstream activation kinase complex component of NF-κB, which function additively in iNKT development and in promoting balanced iNKT1/iNKT2 differentiation. In addition, miR-155 also targeted Rictor, a signature component of mTORC2 that controls iNKT17 differentiation. Taken together, our results indicate that miR-155 serves as a key epigenetic regulator, coordinating multiple signaling pathways and transcriptional programs to precisely regulate iNKT cell development and functional lineage, as well as secondary innate CD8 T cell development.

Highlights

Invariant natural killer T cells are innate-like T cells, which possess the properties of both T cells and NK cells, as they coexpress a rearranged T cell receptor (TCR) and several NK cell receptors, including NK1.1. invariant natural killer T (iNKT) cells are restricted to the non-classical MHCI-like molecule CD1d and preferentially use an invariant TCR consisting predominantly of MicroRNA-155 in iNKT Cell Development the Vα14-Jα18/Vβ8 pair in mice, endowing iNKT cells with specificity for self or non-self-glycolipid antigens (Bendelac et al, 2007; Das et al, 2010)
MiR-155 was detected in all developmental stages of iNKT cells, and expression was dramatically decreased during iNKT cell development, almost to the lowest level at the terminal developmental stage 3 (Figure 1A)
These findings indicated that miR-155 is expressed in a stage-specific pattern in iNKT cells and that miR-155 expression is significantly repressed in mature iNKT cells

Summary

Introduction

Invariant natural killer T (iNKT) cells are innate-like T cells, which possess the properties of both T cells and NK cells, as they coexpress a rearranged T cell receptor (TCR) and several NK cell receptors, including NK1.1. iNKT cells are restricted to the non-classical MHCI-like molecule CD1d and preferentially use an invariant TCR consisting predominantly of MicroRNA-155 in iNKT Cell Development the Vα14-Jα18/Vβ8 pair in mice, endowing iNKT cells with specificity for self or non-self-glycolipid antigens (Bendelac et al, 2007; Das et al, 2010). Unlike conventional T cells, iNKT cells acquire an effector function and differentiate into iNKT1 (PLZFloTbethi), iNKT2 (PLZFhiRORγt−), and iNKT17 (PLZFintRORγt+) based on transcriptional factors, including T-bet, PLZF, GATA3, and RORγt, before thymic export. INKT1/2/17cells rapidly secrete a broad range of cytokines such as IFN-γ, IL-4, and IL-17, respectively, which mediates functions that link innate and acquired immunity in a broad spectrum of diseases, including infection, cancer, allergy, and autoimmunity (Lee et al, 2013). A core transcription factor network necessary for iNKT cell development and functional lineage differentiation has been described. How these transcriptional factors are integrated in posttranscriptional and epigenetic programs and what the detailed underlining molecular networks are remained to be explored

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