Feedback regulation of VISTA and Treg by TNF-α controls T cell responses in drug allergy.

Abstract

Severe cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life-threatening conditions with a mortality of 4%-20%. The clinical application of tumor necrosis factor-alpha (TNF-α) antagonist improves the outcome of some SCARs patients; however, this is complicated by the elusive and varied immunopathogenesis. To clarify the precise process and optimize the therapy regimen of SCARs, we performed single-cell sequencing, in vitro functional and clinical analysis of patients with SCARs. We observed that TNF-α breaks drug-specific T-cell tolerance by inhibiting the expression of V-type immunoglobulin domain-containing suppressor of T-cell activation (VISTA). Furthermore, TNF-α generated a positive feedback loop in the early phase of drug-specific T-cell activation, whereby B cells acted reciprocally on the corresponding T cells to reinforce TNF-α cytokine expression. In contrast, this pathway of TNF-α-VISTA signaling did not operate in memory effector T cells. Drug-specific memory effector T-cell responses were inhibited by increasing Treg cell expression in a negative feedback loop, with TNF-α antagonists preventing the inhibitory effect. These observations align with the clinical analysis that early but not late intervention with TNF-α antagonists significantly improved outcomes in SCARs patients. Our findings defining feedback regulation of VISTA and Treg cells by TNF-α in different stages of the drug-specific T-cell response and, indicate that a Treg agonists, instead of TNF-α antagonists, could be used for treatment of patients with progressive SCARs.