ATAC-seq comparing CD4CD38low vs CD4CD38high T cells from healthy donors and SLE

CD38 has emerged as a potential therapeutic target for patients with systemic lupus erythematosus (SLE) but it is not known whether CD38 alters CD4+ T cell function. Using primary human T cells and CD38-sufficient and -deficient Jurkat T cells, we demonstrate that CD38 shifts the T cell lipid profile of gangliosides from GM3 to GM2 by upregulating B4GALNT1 in a Sirtuin 1-dependent manner. Enhanced expression of GM2 causes ER stress by enhancing Ca2+ flux through the PLC_1-IP3 pathway. Interestingly, correction of the calcium overload by an IP3 receptor inhibitor, but not by a store-operated calcium entry (SOCE) inhibitor, improves IL-2 production by CD4+ T cells in SLE. This study demonstrates that CD38 affects calcium homeostasis in CD4+ T cells by controlling cell membrane lipid composition that results in suppressed IL-2 production. CD38 inhibition with biologics or small drugs should be expected to benefit patients with SLE. Overall design: Biological triplicates of sorted CD38high and low T cells from HC and from SLE patients

CD38已成为系统性红斑狼疮（systemic lupus erythematosus, SLE）患者潜在的治疗靶点，但目前尚不清楚CD38是否会调控CD4阳性T细胞的功能。本研究采用原代人T细胞及CD38正常表达与基因敲除的Jurkat T细胞，证实CD38可通过沉默信息调节因子1（Sirtuin 1）依赖的方式上调B4GALNT1的表达，将T细胞神经节苷脂的脂质谱从GM3转向GM2。GM2表达升高可通过增强经PLC-1-三磷酸肌醇（IP3）通路的钙离子流，诱发内质网应激。值得注意的是，使用三磷酸肌醇受体抑制剂可逆转钙超载，而钙池操纵性钙内流（store-operated calcium entry, SOCE）抑制剂则无此效果，该处理可改善SLE患者CD4阳性T细胞的白细胞介素2（IL-2）分泌水平。本研究证实，CD38可通过调控细胞膜脂质组成影响CD4阳性T细胞的钙稳态，进而抑制IL-2的产生。采用生物制剂或小分子药物抑制CD38，有望使SLE患者获益。整体实验设计：从健康对照（Healthy Control, HC）及SLE患者体内分选得到CD38高表达与低表达的T细胞，每组设置3次生物学重复。