Double-negative T cells in systemic lupus erythematosus: From immunopathology to therapeutic target.

Systemic lupus erythematosus (SLE) is an autoimmune disease marked by diverse clinical manifestations and profound immune dysregulation. Among the immune cells implicated in SLE pathogenesis, double-negative T (DNT) cells, a unique subset of CD3+ T lymphocytes that lack both CD4 and CD8 co-receptors, have emerged as important and context-dependent contributors to disease progression. Pathogenic DNT cells are markedly expanded in SLE patients and disrupt immune tolerance by promoting the production of pathogenic autoantibodies, sustaining chronic inflammation, and directly contributing to tissue injury, particularly in severe manifestations such as lupus nephritis. SLE-associated DNT cells are frequently shaped by inflammatory cytokine milieus and convergent signaling-metabolic hubs (including mechanistic target of rapamycin, mTOR), which help stabilize pathogenic states. Current SLE management, heavily reliant on broad immunosuppression, remains challenged by heterogeneity and limited efficacy. Recent insights into DNT cell biology suggest that targeting pathogenic DNT phenotypes while preserving immunoregulatory subsets may enable a shift from non-specific immunosuppression toward the restoration of immune tolerance. Consequently, DNT cells represent not only key pathogenic effectors in specific inflammatory contexts but also promising biomarkers and therapeutic targets. Because no single surface marker reliably discriminates pathogenic from regulatory DNT states, translational efforts should prioritize multi-parameter phenotyping (e.g., checkpoint and activation markers with differentiation and proliferation states) coupled to functional readouts (IL-17 versus IL-10). Future investigations should focus on developing DNT-targeted strategies, identifying predictive biomarkers, and rigorously assessing long-term safety, thereby paving the way for precision medicine in systemic autoimmunity.