Functional Overlap of Inborn Errors of Immunity and Metabolism Genes Define T Cell Immunometabolic Vulnerabilities.

Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit clinical annotations. Few genes are assigned to both IEM and IEI, but immunometabolic demands suggest functional overlap is underestimated. We applied CRISPR screens to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM showed N-linked glycosylation and the hexosamine synthesis enzyme, , are critical for T cell expansion and function. Interestingly, -deficient T 1 cells were more affected than T 17 cells, which had increased for salvage UDP-GlcNAc synthesis. Screening IEI genes showed the transcription factor promotes CD4 T cell mitochondrial activity and expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and point to potential immunometabolic mechanisms for a previously unappreciated set of these disorders.