Abstract Text: Inborn Errors of Metabolism (IEM) and Immunity (IEI) are Mendelian diseases in which complex phenotypes and patient rarity can limit complete understanding of the full clinical impact of the molecular defect. The genetic overlap of recognized IEM and IEI is currently narrow, but immunometabolic demands of the immune system suggest functional overlap is underestimated. We performed CRISPR screens in mouse CD4+ T cells to test IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable crossover. Analysis of IEM genes showed that N-linked glycosylation and the de novo hexosamine synthesis enzyme, Gfpt1, are critical for T cell expansion and function. Interestingly, TH1 cells were more reliant on Gfpt1 than TH17 cells, which expressed higher levels of Nagk for salvage UDP-GlcNAc synthesis. Conversely, screening IEI genes identified the transcription factor Bcl11b as a metabolic regulator. Bcl11b promotes CD4+ T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Notably, mitochondrial deficiencies were also observed in developing T cells in the thymus of Bcl11b conditional knockout mice, corresponding to impaired T cell development. 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.
