CD38 controls IL-2 production in CD4 T cells

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: Total RNA was extracted from JurkatControl and JurkatCD38KO using the RNeasy mini kit (QIAGEN) and submitted for RNA sequencing to the Molecular Biology Core Facilities at the Dana-Farber Cancer Institute (DFCI). Libraries were prepared using Illumina TruSeq Stranded mRNA sample preparation kits according to the manufacturer's protocols. Samples were sequenced on an Illumina NextSeq500 run with single-end 75-bp reads. Data analyses were performed using the VIPER pipeline by the DFCI Core.