The gastrointestinal microenvironment, dominated by dietary compounds and the commensal bacteria, is a major driver of intestinal CD4⁺ T helper (Th) cell differentiation. Dietary compounds can be sensed by nuclear receptors (NRs) that consequently exert pleiotropic effects including immune modulation. Here, we found that under homeostatic conditions the NR Liver X receptor (LXR), a sensor of cholesterol metabolites, regulates RORγt⁺ CD4 T cells in the intestine draining mesenteric lymph node (MLN). While LXR activation led to a decrease, LXR-deficiency resulted in an increase in MLN Th17 and RORγt⁺ Tregs. Mechanistically, LXR signaling in CD11c⁺ myeloid cells was required to control RORγt⁺ Treg. By contrast, modulation of MLN Th17 was independent of LXR signaling in either immune or epithelial cells. Of note, horizontal transfer of microbiota between LXRα^−/− and WT mice was sufficient to only partially increase MLN Th17 in WT mice. Despite LXRα deficiency resulted in an increased abundance of Ruminococcaceae and Lachnospiraceae bacterial families compared to littermate controls, microbiota ablation (including SFB) was not sufficient to dampen LXRα-mediated expansion of MLN Th17. Altogether, our results suggest that LXR modulates RORγt⁺ Treg and Th17 cells in the MLN through distinct mechanisms.

以膳食化合物和共生细菌为主的胃肠道微环境是肠道 CD4 ⁺ T 辅助 (Th) 细胞分化的主要驱动力。膳食化合物可以被核受体 (NR) 感知，从而发挥多效性作用，包括免疫调节。在这里，我们发现在稳态条件下，胆固醇代谢物的传感器 NR 肝 X 受体 (LXR) 调节肠系膜淋巴结 (MLN) 中的RORγt ^{+ CD4 T 细胞。}虽然 LXR 激活导致减少，但 LXR 缺陷导致 MLN Th17 和 RORγt ⁺ Tregs 增加。^{从机制上讲，需要 CD11c +}骨髓细胞中的 LXR 信号来控制 RORγt ⁺调节剂。相比之下，MLN Th17 的调节独立于免疫细胞或上皮细胞中的 LXR 信号。值得注意的是，LXRα ^-/-和 WT 小鼠之间微生物群的水平转移足以仅部分增加 WT 小鼠的 MLN Th17。尽管与同窝对照相比，LXRα 缺乏导致瘤胃球菌科和毛螺菌科细菌的丰度增加，但微生物群消融（包括 SFB）不足以抑制 LXRα 介导的 MLN Th17 扩增。总之，我们的结果表明 LXR 通过不同的机制调节 MLN 中的 RORγt ⁺ Treg 和 Th17 细胞。