Tfam-mediated metabolic perturbation in RORγt+ lymphocytes impacts intestinal tissue homeostasis and promotes GATA3+RORγt+ innate lymphoid cells

Abstract

Rorc-mediated deletion of Tfam, a mitochondrial transcription factor, causes tuft cell and type 2 immunity-driven small intestine (SI) lengthening in mice. Here, we report an indispensable role for T helper 2 (Th2) cells in this process. High-fat diet (HFD) reverts SI lengthening in Tfam^f/fRorc-cre mice by suppressing IL-13-producing Th2 cells and IL-17-producing Th2 cells and group 2 innate lymphoid cells (ILC2s). HFD reduces conventional GATA3^-/loRORγt⁺ ILC3s but promotes GATA3⁺RORγt⁺ ILCs, especially in Tfam^f/fRorc-cre mice. Compared with conventional ILC3s, GATA3⁺RORγt⁺ ILCs express type 2 cytokines and increase cell proliferation but decrease cell death with metabolic re-programming. Single-cell transcriptional analyses indicate that GATA3⁺RORγt⁺ ILCs represent a distinct population, different from IL-17^- natural ILC2s, IL-17⁺ inflammatory ILC2s, or conventional ILC3s. GATA3⁺RORγt⁺ ILCs produce IL-17 but not IL-22, resulting from competition of the aryl hydrocarbon receptor (Ahr) with GATA3 at the Il22 locus. Tfam^f/fRorc-cre mice on HFD have worsened dextran sodium sulfate (DSS)-induced colitis. These data highlight the role of ILC metabolism in intestinal tissue remodeling and inflammation.

Keywords: CP: immunology; CP: metabolism; ILCs; Tfam; colitis; high-fat diet; metabolic dysfunction; small intestine lengthening.