Project Summary Discovery of the genetic basis of inborn errors of immunity in humans provides impactful information about genes, proteins, and pathways that are fundamentally important for healthy immune function. Inflammation is a critical component of immune activation that normally signals the presence of microbes to initiate molecular and cellular responses required to contain and eliminate a pathogen. However, aberrantly high inflammation is detrimental to host fitness and contributes to pathology in an array of human diseases. In order to control inflammation, there are many intracellular and secreted anti-inflammatory proteins that are transcribed in a cell- type and context-dependent manner. A prime example is IL-10, which when defective in humans causes monogenic very early-onset IBD. However, there is relatively limited knowledge about transcription factors that act as master regulators of these inducible anti-inflammatory genes in humans. We have now discovered a new human inborn error of immunity caused by novel loss-of-function mutations in the ELF4 transcription factor gene that we hypothesize serves as a master regulator at the intersection of interferon, inflammasome, and Th17 biology. The three patients identified through our genomics program suffer from mucosal autoinflammation with IBD features, fever, and oral ulcers, and we have now generated powerful Elf4 knockout, point mutant, and floxed mouse models to advance our knowledge. Our preliminary data in ELF4-mutant human and mouse cells emphasize cell type-specific functions of this factor, with increased inflammatory responses in myeloid and T cells associated with failed anti-inflammatory gene expression programs. We will pursue two aims to illuminate how ELF4 functions as a cornerstone in the cross-regulation of interferon, inflammasome, and Th17 responses. Aim 1) Dissect molecular and biochemical effects of WT and mutant ELF4 in myeloid and Th17 cells. Aim 2) Define the roles of WT and mutant ELF4 in cellular and organismal inflammatory responses mediated by myeloid and Th17 cells. The results of these investigations will provide invaluable new insights with direct relevance for understanding the etiology and devising targeted therapy in this new human disorder and, by extension, more broadly in prevalent inflammatory diseases.