CD38 in SLE CD4 T cells promotes Ca2+ flux and suppresses interleukin-2 production by enhancing the expression of GM2 on the surface membrane
Eri Katsuyama, Morgane Humbel, Abel Suárez‐Fueyo, Abhigyan Satyam, Nobuya Yoshida, Vasileios C. Kyttaris, Maria Tsokos, George C. Tsokos
Abstract
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 CD38-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 PLCγ1-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. CD38 has been reported to be upregulated on T cells in lupus with unclear functional consequences. Here the authors show that CD4+CD38+ T cells from lupus patients have altered calcium homeostasis accompanied by alteration in cell membrane lipid composition and a suppression of IL-2.