12R-HETE acts as an endogenous ligand for Nur77 in the intestines and regulates NKp46⁺ ILC3 development.

Abstract

How intestinal immunity develops during early life remains a key question in understanding defense against infections. Group 3 innate lymphoid cells (ILC3s) are critical for this defense, and their developmental progression and subset balance are essential for effective immune function. Here, we show that the nuclear receptor Nur77 helps control NKp46⁺ ILC3 development in newborn mice. Mice lacking Nur77 have fewer ILC3s and failed to convert one ILC3 subtype (NKp46^-) into a more protective form (NKp46⁺), reducing their ability to fight <i>Salmonella enterica</i> serovar Typhimurium infection. We found that 12R-hydroxyeicosatetraenoic acid (12R-HETE), a natural lipid found in the intestine, binds to Nur77 and boosts the expression of transcription factor T-box expressed in T cells (T-bet), promoting the shift to NKp46⁺ ILC3s and increasing the production of interferon-γ (IFN-γ), a key immune molecule. This response is dependent on Nur77. Further analyses have revealed that Nur77 directly regulates a gene called <i>Impdh1</i>, which supports this immune transition. Our findings uncover a Nur77-driven pathway that helps shape gut immunity in early life.