Abstract
ObjectivesType I interferons (IFNs) inhibit regulatory T‐cell (Treg) expansion and activation, making them beneficial in antiviral responses, but detrimental in autoimmune diseases. Herein, we investigate the role of ISG15 in human Tregs in the context of refractoriness to type I IFN stimulation.MethodsISG15 expression and Treg dynamics were analysed in vitro and ex vivo from patients with chronic hepatitis C, with lupus and ISG15 deficiency.ResultsISG15 is expressed at high levels in human Tregs, renders them refractory to the IFN‐STAT1 signal, and protects them from IFN‐driven contraction. In vitro, Tregs from healthy controls upregulate ISG15 upon activation to higher levels than conventional CD4 T cells, and ISG15‐silenced Tregs are more susceptible to IFNα‐induced contraction. In human ISG15 deficiency, patient Tregs display an elevated IFN signature relative to Tregs from healthy control. In vivo, in patients with chronic hepatitis C, 2 days after starting pegIFN/ribavirin therapy, a stronger ISG15 inducibility correlates with a milder Treg depletion. Ex vivo, in systemic lupus erythematosus patients, higher levels of ISG15 are associated to reduced STAT1 phosphorylation in response to IFNα, and also to increased frequencies of Tregs, characterising active disease.ConclusionOur results reveal a Treg‐intrinsic role of ISG15 in dictating their refractoriness to the IFN signal, thus preserving the Treg population under inflammatory conditions.
Highlights
Regulatory T cells (Tregs) are devoted to the suppression of potentially harmful immune responses and to the recovery of immune and tissue homeostasis after injuries.[1]
We have previously observed that, in chronic hepatitis C (CHC) patients, Tregs declined as early as 2 days after pegIFN/ribavirin therapy starting and that the induction of several IFN-stimulated genes (ISGs) could be already detected at the same time point in peripheral blood mononuclear cells (PBMCs).[16]
Among the tested ISGs, we noticed that ISG15 expression was more variable among patients at baseline compared to Protein Kinase R (PKR) and Myxovirus resistance protein 1 (MXA) (Figure 1a), in line with previous data.[9]
Summary
Regulatory T cells (Tregs) are devoted to the suppression of potentially harmful immune responses and to the recovery of immune and tissue homeostasis after injuries.[1] To accomplish this function, Tregs rapidly adjust their activities in response to diverse inflammatory signals. These cells constitutively express a variety of receptors for soluble mediators including cytokines. Dysregulation of the type I IFN signalling may play detrimental roles in host defence, promoting immunopathology or even inducing immune suppression.[3] The pathogenic roles of type I IFNs in several autoimmune diseases, and especially systemic lupus erythematosus (SLE), are well established, as documented by the appearance of an IFN-related gene signature in peripheral blood (PB) concomitantly with disease reactivation.[4]
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