Functional Overlap of Inborn Errors of Metabolism and Immunity Genes Identifies CD4+ T Cell immunometabolic Requirements

During the past decade, it has become increasingly apparent that cellular metabolism plays a critical role in the function and regulation of the immune system. Immune cell utilization of specific metabolic pathways influences immune function and can be pharmacologically targeted to alter immune outcomes. The importance of immune cell metabolism and function is further demonstrated by the development of primary immunodeficiencies in patients deficient in certain metabolic pathways. Inborn errors of immunity (IEI) and metabolism (IEM) are Mendelian diseases in which complex phenotypes and patient rarity can limit comprehensive clinical descriptions. Few genes are assigned to both IEM and IEI, but the varied and intensive immunometabolic demands of immune cells suggest greater functional overlap may exist. We applied pooled CRISPR screens to test IEM-associated genes for immunologic roles and IEI-associated genes for metabolic effects in CD4+ T cells and found considerable crossover. Screens of IEM-associated genes showed N-linked glycosylation and the de novo hexosamine biosynthetic enzyme, GFAT (Gfpt1), are critical for CD4+ T cell function. Interestingly, Gfpt1-deficient TH1 cells were more affected than TH17 cells and demonstrated a greater rate of de novo UDP-GlcNAc synthesis. Likewise, screens of IEI-associated genes indicated that the transcription factor BCL11B promotes CD4+ T cell mitochondrial activity and MCL1 expression necessary to prevent metabolic stress. These data illustrate a high degree of functional overlap of IEM and IEI genes and suggest immunometabolic mechanisms for a previously underappreciated set of these disorders.