Lipid droplet-induced T cell death sustains autoimmune tissue inflammation.

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.