TNF‑α blockade reverses Stevens‑Johnson syndrome/toxic epidermal necrolysis through the RORγt/Foxp3‑mediated restoration of T helper 17/regulatory T cell balance

Within the present study, the aim was to examine how the expression of retinoic acid‑related orphan receptor γ‑t (RORγt) and Foxp3 influences the balance between T helper 17 (Th17) cells and regulatory T cells (Tregs) in a mouse model of Stevens‑Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and to determine the association of this mechanism with the therapeutic response to a TNF‑α blockade. A murine SJS/TEN model was induced and animals were assigned to three groups: Disease model, TNF‑α inhibitor treatment and healthy control. The analytical methods conducted included histopathology (H&E and toluidine blue staining), measurement of serum cytokines using ELISA, flow cytometric quantification of Th17 and Treg frequencies in peripheral blood, immunohistochemical (IHC) evaluation and reverse transcription‑quantitative PCR (RT‑qPCR) analysis of RORγt and Foxp3 expression in isolated CD3⁺ T lymphocytes. Mice in the model group displayed characteristic histopathological features, including widespread epidermal necrosis, dense dermal inflammatory infiltration and increased mast cell counts. Serum concentrations of IL‑17 and IL‑23 were elevated. Immune profiling demonstrated a higher frequency of Th17 cells, a lower frequency of Tregs and a consequently increased Th17/Treg ratio. Both IHC and RT‑qPCR data indicated marked upregulation of RORγt and downregulation of Foxp3 at both protein and transcriptional levels. Treatment with a TNF‑α inhibitor reversed these changes, resulting in ameliorated skin pathology, normalized Th17/Treg balance, reduced RORγt and restored Foxp3 expression. The degree of Foxp3 restoration and Th17/Treg rebalancing were positively correlated with a clinical improvement in skin lesions. Overall, disruption of Th17/Treg equilibrium, driven by dysregulation of the RORγt/Foxp3 axis within CD3⁺ T cells, was found to be a key mechanism in SJS/TEN pathogenesis. TNF‑α blockade exerts its therapeutic effect by transcriptionally reprogramming T cells, directly suppressing the expression of RORγt while promoting the expression of Foxp3. This bidirectional regulation corrects the Th17/Treg imbalance. These findings demonstrate the important immunomodulatory action of TNF‑α inhibition and offer preclinical support for its use in SJS/TEN, while suggesting potential biomarkers for monitoring treatment efficacy.