Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism

Zheng Fu, Joseph W. Dean, Lifeng Xiong, Michael W. Dougherty, Kristen N. Oliff, Zong-ming E. Chen, Christian Jobin, Timothy J. Garrett and Liang Zhou ()
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Zheng Fu: University of Florida
Joseph W. Dean: University of Florida
Lifeng Xiong: University of Florida
Michael W. Dougherty: University of Florida
Kristen N. Oliff: University of Florida
Zong-ming E. Chen: Mayo Clinic
Christian Jobin: University of Florida
Timothy J. Garrett: University of Florida
Liang Zhou: University of Florida

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24755-9

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