Inborn errors of metabolism (IEMs) and inborn errors of immunity (IEIs) are human monogenic disorders caused by germline variants in single genes. A deeper understanding of these diseases could lead to new therapeutic options as well as revealing the basic biology underpinning the disorders. In Science Immunology, Patterson et al. use CRISPR screens of known IEM and IEI genes to test whether these have roles in the immune response, and find that N-linked glycosylation and the hexosamine pathway gene Gfpt1 are required for T cell function and link Bcl11b with mitochondrial activity. Pooled CRISPR libraries were created that target disease-relevant genes, and tested for overlap in immune and metabolic regulatory mechanisms in mouse CD4 T cells. The N-glycan biosynthesis pathway was identified as crucial for T cell expansion and survival, specifically the GFPT1 enzyme, and was required for the expansion of T helper 1 (T_H1) and T_H17 cells and polarization of T_H1 cells. BCL11B was identified as a regulator of metabolic activity in activated CD4 T cells. Bcl11b-deficient CD4 T cells had reduced expression of MYC and MCL1, which resulted in reduced mitochondrial mass, mitochondrial membrane potential and levels of reactive oxygen species. Further study of genes from such screens may provide important insights into the immunometabolic mechanisms of disease.

Original reference: Sci. Immunol. https://doi.org/10.1126/sciimmunol.adh0368 (2024)

先天性代谢缺陷 （IEM） 和先天性免疫缺陷 （IEI） 是由单个基因中的种系变异引起的人类单基因疾病。对这些疾病的更深入理解可能会带来新的治疗选择，并揭示支撑这些疾病的基本生物学。在《科学免疫学》中，Patterson 等人使用已知 IEM 和 IEI 基因的 CRISPR 筛选来测试它们是否在免疫反应中发挥作用，并发现 N-连接糖基化和己糖胺通路基因 Gfpt1 是 T 细胞功能所必需的，并将 Bcl11b 与线粒体活性联系起来。创建了靶向疾病相关基因的混合 CRISPR 文库，并测试了小鼠 CD4 T 细胞中免疫和代谢调节机制的重叠。N-糖生物合成途径被确定为 T 细胞扩增和存活的关键，特别是 GFPT1 酶，并且是辅助性 T 细胞 1 （T_H1） 和 T_H17 细胞扩增以及 T_H1 细胞极化所必需的。BCL11B 被确定为活化 CD4 T 细胞中代谢活性的调节因子。Bcl11b 缺陷型 CD4 T 细胞 MYC 和 MCL1 表达降低，导致线粒体质量、线粒体膜电位和活性氧水平降低。对此类筛选中的基因的进一步研究可能为疾病的免疫代谢机制提供重要见解。

Original reference: Sci. Immunol. https://doi.org/10.1126/sciimmunol.adh0368 (2024)