Type I interferons (IFN-I) are multifunctional cytokines that act locally and systemically in many physiological and pathological processes, sometimes in a paradoxical way. Although widely used in clinical application, IFN-I can become pathogenic in chronic infections and in autoimmune and inflammatory diseases. Our Unit investigates cell-intrinsic molecular mechanisms mediating and regulating IFN-I responses in human cells. We also focus on the direct effect of IFN-I on T cell-mediated immune response and on the impact of TYK2 variants in autoimmunity. We deem that knowledge of signaling mechanisms ensuring a balanced IFN-I response and return to homeostasis is essential to understand immunological processes and to translation into clinical application. Our recent study of ISG15-deficient patients illustrates how disruptive the lack of a subtle signaling retrocontrol can be to the equilibrium of the immune system. As a whole, our research aims at bridging molecular analysis to human physiology and pathogenesis. Conceptually, our findings can serve as paradigm for other cytokine systems and may direct the development of innovative therapeutics to better utilize IFN or to target its activity.
TYK2 variants in cytokine signaling and autoimmune diseases
TYK2 belongs to the Janus/JAK family of protein tyrosine kinases and is involved in signaling of immunoregulatory cytokines (type I and type III IFNs, IL-6, IL-10 and IL-12 families) that contribute to a balanced […]
IFN-I and translational control
We have investigated whether IFN-I activates the mTOR translational control pathway and to what extent the control of mRNA translation contributes to IFN α2/β responses. General questions have been addressed by a genome-wide search […]
Exploring a link between ISGylation and cell cycle via SKP2
We recently uncovered a potentially interesting connection between ISGylation and cell cycle regulation. We reported that the degradation of USP18, major negative regulator of IFN-I signaling, involves SKP2, a well known actor in cell […]
ISG15 contribution to tuning of IFN-I activity and interferonopathies
We have reported on the implication of the ubiquitin-like ISG15 protein in the negative regulation of IFN-I response in humans. ISGylation is a major post-translational modification whereby numerous proteins are conjugated to ISG15, with […]
Fine-tuning of IFN-I response by USP18
The type I IFN system needs to be regulated not only at the level of its production, but also at the level of responses. We have shown that cells that have responded to IFN-I […]
Cellular and molecular immunoprofiling of multiple sclerosis patients
This project aims at providing new knowledge on the immunomodulatory effect of IFN-I in multiple sclerosis patients by using state-of-the-art technologies. An important challenge is the identification of cellular and molecular biomarkers of IFN […]
Role of IFN-I in the development of IL-10-producing CD4 T cells
We have shown that IFN-I promotes development of human type 1 regulatory-like cells (Tr1) that produce the anti-inflammatory cytokine IL-10, and have studied the integration of T cell receptor (TCR) signal strength and CD28 […]
2020Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage, PLoS ONE 2020;15(1):e0225289.
2019USP18 and ISG15 coordinately impact on SKP2 and cell cycle progression, Sci Rep 2019 Mar;9(1):4066.
2018Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant, Sci Immunol 2018 Dec;3(30).
2018Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds, PLoS ONE 2018;13(10):e0205826.
2018Thymosins in multiple sclerosis and its experimental models: moving from basic to clinical application, Mult Scler Relat Disord 2019 Jan;27:52-60.
2017Esx Factors Control Human Dendritic Cell Functions Conditioning Th1/Th17 Response, Front Cell Infect Microbiol 2017;7:330.
2017Type I interferon-enhanced IL-10 expression in human CD4 T cells is regulated by STAT3, STAT2, and BATF transcription factors, J. Leukoc. Biol. 2017 05;101(5):1181-1190.
2017STAT2 is an essential adaptor in USP18-mediated suppression of type I interferon signaling, Nat. Struct. Mol. Biol. 2017 Mar;24(3):279-289.
2017Thymosin-α1 expands deficient IL-10-producing regulatory B cell subsets in relapsing-remitting multiple sclerosis patients, Mult. Scler. 2018 Feb;24(2):127-139.
2017Worldwide Epidemiology and Antibiotic Resistance of Staphylococcus aureus, Curr. Top. Microbiol. Immunol. 2017;409:21-56.
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