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

ROR gamma t is known to play critical roles in the regulation of a number of immune cell subsets. Here the authors implicate mitochondrial transcription factor A in the regulation of intestinal ROR gamma t( +) lymphocyte homeostasis and metabolic control in a murine in vivo model. ROR gamma t(+) lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (gamma delta T17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, gamma delta T17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal gamma delta T17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in ROR gamma t(+) lymphocytes significantly affects systemic gamma delta T17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in ROR gamma t(+) lymphocytes, especially in gamma delta T17 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 ROR gamma t(+) 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.

Automated summary

The authors found that mitochondrial transcription factor A plays a crucial role in regulating intestinal RORγt(+) lymphocyte homeostasis and metabolic control in mice. Deletion of Tfam affects the maintenance of γδT17 cells and the number of ILC3s, leading to intestinal tissue remodeling and growth.