Mitochondrial transcription factor A in ROR\u03b3t+ lymphocytes regulate small intestine homeostasis and metabolism

Zheng Fu,Joseph W Dean,Zong-Ming E Chen,Liang Zhou,Lifeng Xiong,Kristen N Oliff,Michael W Dougherty,Christian Jobin,Timothy J Garrett

doi:10.1038/s41467-021-24755-9

Zheng Fu, Joseph W Dean + Show 7 more

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https://doi.org/10.1038/s41467-021-24755-9

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Journal: Nature Communications	Publication Date: Jul 22, 2021
Citations: 17	License type: open-access

Affiliation: University of Florida, Mayo Clinic

Abstract

RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.

Highlights

RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators
Compared to Th17 cells and ILC3s, little is known about metabolic regulation of γδT17 cells
Overexpression of IL-22 in vivo in Tfamfl/flRorc-cre mice by hydrodynamic injection reduced the expression of tuft cell and type 2 immune genes and restored the small intestine length (Fig. 6h, i). These results suggest that the phenotypes of small intestine tissue remodeling upon ablation of Tfam in RORγt+ lymphocytes are at least in part due to lack of IL-22, a cytokine that suppresses the intestinal tuft cell–ILC2 circuit

Summary

Introduction

RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. These mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling. Tfam is a nuclear gene encoding transcription factor crucial for mitochondrial DNA replication and transcription[17,18,19]

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