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

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.619220

DOI=10.3389/fcell.2020.619220

ISSN=2296-634X

ABSTRACT=<p>The development of invariant natural killer T (<italic>i</italic>NKT) 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 <italic>i</italic>NKT cells upon thymic selection, and then its expression is gradually downregulated during <italic>i</italic>NKT cell development. However, the mice with miR-155 germline deletion had normal <italic>i</italic>NKT cell development. To address if downregulated miR-155 is required for <italic>i</italic>NKT 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 <italic>i</italic>NKT cell development, diminished <italic>i</italic>NKT17 and <italic>i</italic>NKT1 cells, augmented <italic>i</italic>NKT2 cells, and these defects were cell intrinsic. Furthermore, defective <italic>i</italic>NKT 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 <italic>i</italic>NKT cell development. MiR-155 modulated <italic>Jarid2</italic>, a critical component of a histone modification complex, and <italic>Tab2</italic>, the upstream activation kinase complex component of NF-κB, which function additively in <italic>i</italic>NKT development and in promoting balanced <italic>i</italic>NKT1/<italic>i</italic>NKT2 differentiation. In addition, miR-155 also targeted <italic>Rictor</italic>, a signature component of mTORC2 that controls <italic>i</italic>NKT17 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 <italic>i</italic>NKT cell development and functional lineage, as well as secondary innate CD8 T cell development.</p>