Liver X Receptor regulates Th17 and RORγt⁺ Treg cells by distinct mechanisms

Abstract

22The gastrointestinal microenvironment, dominated by dietary compounds and the commensal bacteria, 23 is a major driver of intestinal CD4 + T helper (Th) cell differentiation. Dietary compounds can be sensed 24 by nuclear receptors (NRs) that consequently exerts pleiotropic effects including immune modulation. 25However, how NRs regulate distinct intestinal Th subsets remain poorly understood. Here, we found 26 that under homeostatic condition Liver X receptor (LXR), a sensor of cholesterol metabolites, controls 27RORγt + Treg and Th17 cells in the intestine draining mesenteric lymph node (MLN). Mechanistically, 28 while lack of LXR signaling in CD11c + myeloid cells led to an increase in RORγt + Treg, modulation 29 of MLN Th17 was independent of LXR signaling in either immune or epithelial cells. Of note, LXRα 30 modulated only the Th17 cells, but not RORγt + Treg in the MLN and horizontal transfer of microbiota 31 between LXRα −/− and WT mice was sufficient to partially increase the MLN Th17 in WT mice. While 32LXRα deficiency increased the abundance of Ruminococcaceae and Lachnospiraceae bacterial 33 families compared to the WT littermates, microbiota ablation including ablation of SFB was not 34 sufficient to dampen LXRα-mediated expansion of MLN Th17. Altogether, our results suggest that 35 LXR modulates RORγt + Treg and Th17 cells in the MLN through distinct mechanisms.The intestinal barrier is continuously exposed to the changing external environment. To face this 56 challenge, our immune system has evolved to rapidly adapt to environmental changes by mounting 57 tolerogenic and effector responses on demand. A dynamic equilibrium between these two arms of the 58 immune system is required to maintain homeostasis, and failure of mounting an appropriate regulatory 59 response may lead to uncontrolled inflammatory reactions and chronic immune disorders. 60Owing to their ability to react in an antigen-specific manner CD4 + T helper (Th) cells are central 61 players in ensuring a protective response while limiting collateral damage. Mounting a functional Th 62 cell response in the intestine relies on the anatomical distribution of T cells in immunological inductive 63 and effector sites, where the former is constituted by intestine-draining lymphoid structures such as 64 MLN and the latter being the intraepithelial and lamina propria compartments 1 . The inductive sites 65 represent the arena where naïve CD4 + T cells encounter their cognate antigens for the first time and 66 functionally commit to specific effector subsets. Under steady state, retinoic acid-related orphan 67 receptor gt (RORgt) + Th cells (Th17) and Foxp3 expressing regulatory T cells (Treg) are the most 68 represented Th subsets in the MLN. Despite a certain degree of lineage and functional flexibility, Th17 69 and Treg cells play complementary roles in maintaining intestinal homeostasis. Although the 70 expression of RORgt and Foxp3 was originally thought to be mutually exclusive, a distinct new 71 population of RORgt + Foxp3 + regulatory T ...