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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Eri Katsuyama & Morgane Humbel & Abel Suarez-Fueyo & Abhigyan Satyam & Nobuya Yoshida & Vasileios C. Kyttaris & Maria G. Tsokos & George C. Tsokos, 2024. "CD38 in SLE CD4 T cells promotes Ca2+ flux and suppresses interleukin-2 production by enhancing the expression of GM2 on the surface membrane," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52617-7
    DOI: 10.1038/s41467-024-52617-7
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    References listed on IDEAS

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    1. Murali Prakriya & Stefan Feske & Yousang Gwack & Sonal Srikanth & Anjana Rao & Patrick G. Hogan, 2006. "Orai1 is an essential pore subunit of the CRAC channel," Nature, Nature, vol. 443(7108), pages 230-233, September.
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    3. Mulki Angela & Yusuke Endo & Hikari K. Asou & Takeshi Yamamoto & Damon J. Tumes & Hirotake Tokuyama & Koutaro Yokote & Toshinori Nakayama, 2016. "Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells," Nature Communications, Nature, vol. 7(1), pages 1-15, December.
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