2. Academic Validation
  3. Lipid droplet-induced T cell death sustains autoimmune tissue inflammation

Lipid droplet-induced T cell death sustains autoimmune tissue inflammation

  • Cell Metab. 2026 Apr 7;38(4):694-711.e8. doi: 10.1016/j.cmet.2026.01.014.
Jitendra Kumar 1,  Yoshinori Takashima 1,  Jose Morales 1,  Brandon Wong 1,  Lina Werner 1,  Isabel N Goronzy 2,  Selene Rubino 3,  Robert T Trousdale 4,  Gerald J Berry 5,  Jörg J Goronzy 6,  Cornelia M Weyand 7
Affiliations

Affiliations

  • 1 Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Cardiovascular Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA.
  • 2 Division of Biology and Bioengineering, California Institute of Technology, Pasadena, CA, USA; Yale School of Medicine, New Haven, CT, USA.
  • 3 Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
  • 4 Department of Orthopedic Surgery, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
  • 5 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 6 Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 7 Department of Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA; Department of Cardiovascular Medicine, Mayo Clinic Alix School of Medicine, Rochester, MN 55905, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: [email protected].
PMID: 41713424 DOI: 10.1016/j.cmet.2026.01.014
Abstract

Autoimmunity leading to rheumatoid arthritis (RA) involves CD4+ T cell recruitment into synovial tissue. However, metabolic conditions supporting the survival and pro-inflammatory effector functions of these tissue-invading T cells remain poorly understood. Lipidomic analysis identified the inflamed synovium as a lipid-rich environment. In functional studies, administration of the free fatty acid oleic acid exacerbated synovitis. Tissue-invading CD4+ T cells responded to fatty acid with rapid Cell Lysis, releasing cytoplasmic and nuclear content into the extracellular space. This T cell lytic death required sequestration of the pore-forming molecule gasdermin D and the Acyltransferase zDHHC5 to lipid droplets, which translocated to the plasma membrane to trigger membrane rupture and pyroptotic cell death. Targeting lipid droplet formation in CD4+ T cells through perilipin-2 knockdown or inhibiting gasdermin activation by blocking protein acylation proved highly effective in suppressing synovitis. Thus, autoimmune CD4+ T cells lack metabolic resilience, are primed to undergo Pyroptosis in lipid-rich environments, and deliver pro-inflammatory cargo to surrounding tissue.

Keywords

T cell; autoimmune disease; gasdermin D; inflammation; lipid droplet; protein S-acylation; pyroptosis.

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