Ilenia Pacella1, Francesca Romana Spinelli1, Martina Severa2, Eleonora Timperi1,3, Gloria Tucci1, Marta Zagaglioni1,4, Fulvia Ceccarelli1, Fabiana Rizzo2, Eliana M Coccia2, Roosheel S Patel5,6,7,8,9, Marta Martin-Fernandez5,6,7,8,9, Dusan Bogunovic5,6,7,8,9, Fabrizio Conti1, Vincenzo Barnaba1,4, Silvia Piconese1,4. 1. Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari Sapienza Università di Roma Rome Italy. 2. Department of Infectious Diseases Istituto Superiore di Sanità Rome Italy. 3. Present address: Eleonora Timperi Institut Curie Paris France. 4. Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti Rome Italy. 5. Center for Inborn Errors of Immunity Icahn School of Medicine at Mount Sinai New York NY USA. 6. Precision Immunology Institute Icahn School of Medicine at Mount Sinai New York NY USA. 7. Mindich Child Health and Development Institute Icahn School of Medicine at Mount Sinai New York NY USA. 8. Department of Pediatrics Icahn School of Medicine at Mount Sinai New York NY USA. 9. Department of Microbiology Icahn School of Medicine at Mount Sinai New York NY USA.
Abstract
OBJECTIVES: Type 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. METHODS: ISG15 expression and Treg dynamics were analysed in vitro and ex vivo from patients with chronic hepatitis C, with lupus and ISG15 deficiency. RESULTS: ISG15 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. CONCLUSION: Our results reveal a Treg-intrinsic role of ISG15 in dictating their refractoriness to the IFN signal, thus preserving the Treg population under inflammatory conditions.
OBJECTIVES: Type 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. METHODS: ISG15 expression and Treg dynamics were analysed in vitro and ex vivo from patients with chronic hepatitis C, with lupus and ISG15 deficiency. RESULTS: ISG15 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. CONCLUSION: Our results reveal a Treg-intrinsic role of ISG15 in dictating their refractoriness to the IFN signal, thus preserving the Treg population under inflammatory conditions.
Authors: Julia K Polansky; Karsten Kretschmer; Jennifer Freyer; Stefan Floess; Annette Garbe; Udo Baron; Sven Olek; Alf Hamann; Harald von Boehmer; Jochen Huehn Journal: Eur J Immunol Date: 2008-06 Impact factor: 5.532