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 Suarez-Fueyo, Abhigyan Satyam, Nobuya Yoshida, Vasileios C. Kyttaris, Maria G. Tsokos and George C. Tsokos ()
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Eri Katsuyama: Harvard Medical School
Morgane Humbel: Harvard Medical School
Abel Suarez-Fueyo: Harvard Medical School
Abhigyan Satyam: Harvard Medical School
Nobuya Yoshida: Harvard Medical School
Vasileios C. Kyttaris: Harvard Medical School
Maria G. Tsokos: Harvard Medical School
George C. Tsokos: Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52617-7

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