Overlapping Mendelian disorders of immunity and metabolism shape CD4 +T cell immunometabolism

Abstract

Abstract 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. To identify novel mechanisms governing the interplay between CD4 +T cell metabolism and function, we performed a series of CRISPR screens evaluating CD4 +T cell expansion, substrate uptake, and mitochondrial function. Specifically, we leveraged the Inborn Errors of Metabolism (IEM) and Immunity (IEI) to identify new immunometabolic regulators. Through these screens, I identified the transcription factor Bcl11b as a critical regulator in CD4 +effector T cell mitochondrial metabolism and function. Additional studies suggest Bcl11b plays a key role regulating mitochondria and metabolic stress in activated T cells. Conversely, screens of IEM genes for T cell functional defects showed that the N-linked glycosylation and the entry enzyme for de novohexosamine synthesis, Gfpt1, pathway were essential for CD4 +T cell expansion and survival. Notably, Gfpt1-deficient T H1 cells more affected than T H17 cells, which had greater capacity for salvage UDP-GlcNAc synthesis. This IEM and IEI-based CRISPR screening approach offers a unique opportunity to identify novel genes and regulatory pathways that are critical and sufficient for productive immune responses and to evaluate their effect on immunometabolism. R01 DK105550