Interferon-stimulated Viperin impairs Treg function in autoimmune thrombocytopenia

TL;DR

This study shows how a protein called Viperin, activated by interferon, disrupts the function of regulatory T cells in patients with immune thrombocytopenia, leading to autoimmune platelet destruction.

Contribution

The study identifies the ELF1-Viperin pathway as a novel driver of Treg dysfunction in ITP.

Findings

Tregs in ITP patients show increased interferon signaling and altered subset composition.

Viperin overexpression impairs Treg function and promotes Th1 activation in conventional T cells.

ELF1 activates Viperin transcription through epigenetic modifications.

Abstract

Primary immune thrombocytopenia (ITP) is an autoimmune disorder driven by dysfunctional regulatory T cells (Tregs) that mediate platelet destruction. Here, we show that Tregs from ITP patients undergo a profound shift in subset composition and transcriptional states, with expansion of ANXA1high and IKZF2high populations and aberrant interferon signaling. Single-cell transcriptomic and functional analyses revealed that in normal controls, immature-like Tregs predominantly exhibit a FOXP3high/CCR6high phenotype, whereas in chronic ITP they adopt an ANXA1high state enriched for interferon-stimulated gene (ISG)high subclusters. Elevated ISG scores in chronic ITP Tregs mark a pathological transition, with RSAD2 (Viperin) emerging as a key regulator. Viperin overexpression impaired Treg suppressive function and promoted Th1-skewed activation in conventional T cells. Mechanistically, ELF1 directly binds the RSAD2 promoter and activates its transcription via increased H3K4Me3 deposition. These findings identify the ELF1-Viperin axis as the driver of Treg dysfunction in ITP and a potential target for therapeutic intervention.

The online version contains supplementary material available at 10.1186/s12964-025-02511-6.

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