CD38 in SLE CD4 T cells promotes Ca2+ flux and suppresses interleukin-2 production by enhancing the expression of GM2 on the surface membrane

Nat Commun. 2024 Sep 27;15(1):8304. doi: 10.1038/s41467-024-52617-7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADP-ribosyl Cyclase 1* / genetics
  • ADP-ribosyl Cyclase 1* / metabolism
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / metabolism
  • Calcium* / metabolism
  • Cell Membrane* / metabolism
  • Female
  • Humans
  • Interleukin-2* / metabolism
  • Jurkat Cells
  • Lupus Erythematosus, Systemic* / genetics
  • Lupus Erythematosus, Systemic* / immunology
  • Lupus Erythematosus, Systemic* / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / metabolism

Substances

  • ADP-ribosyl Cyclase 1
  • Calcium
  • CD38 protein, human
  • Interleukin-2
  • Membrane Glycoproteins
  • Phospholipase C gamma
  • IL2 protein, human

Associated data

  • GEO/GSE273008
  • GEO/GSE273009