Autoimmun Rev. 2026 Oct 24:104217. doi: 10.1016/j.autrev.2026.104217. Online ahead of print.
ABSTRACT
Systemic lupus erythematosus (SLE) is a heterogeneous, multisystem autoimmune disease in which the breakdown of T-cell tolerance is increasingly recognized as a central and therapeutically tractable event. Herein, we synthesize the spectrum of T-cell abnormalities in SLE and elucidate the underlying molecular mechanisms. SLE T cells show expanded B-cell-helper (Tfh/Tph), Th17 and double-negative populations, deficient or dysfunctional regulatory T cells, an intrarenal Th1 bias, clonally expanded cytotoxic and tissue-resident memory CD8+ cells, and expanded IL-10-producing Th10 and age-associated helper T-cell states. We propose that these phenotypes arise from four interacting layers of dysregulation: extracellular cues including cytokine and non-cytokine mediators and altered antigen presentation, T-cell receptor (TCR) and co-stimulatory signaling, immunometabolic reprogramming, and epigenetic remodeling spanning DNA methylation, RNA modifications and histone post-translational modifications (PTMs). We highlight an integrated metabolic-epigenetic axis, in which metabolites act as obligatory substrates or cofactors for the enzymes that write and erase chromatin marks, and we identify the PP2A signaling axis, CaMK4 and mTOR as hubs that act across several layers at once, so that the layers are bidirectionally coupled rather than arranged in a single causal direction. Finally, we discuss how these mechanisms inform an evolving therapeutic landscape.
PMID:42925994 | DOI:10.1016/j.autrev.2026.104217