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van der Vlist M, Ramos MIP, van den Hoogen LL, et al. Signaling by the inhibitory receptor CD200R is rewired by type I interferon. Sci Signal. 2021;14(704):eabb4324doi: 10.1126/scisignal.abb4324.
van der Vlist, M., Ramos, M. I. P., van den Hoogen, L. L., Hiddingh, S., Timmerman, L. M., de Hond, T. A. P., Kaan, E. D., van der Kroef, M., Lebbink, R. J., Peters, F. M. A., Khoury-Hanold, W., Fritsch-Stork, R., Radstake, T. R. D. J., & Meyaard, L. (2021). Signaling by the inhibitory receptor CD200R is rewired by type I interferon. Science signaling, 14(704), eabb4324. https://doi.org/10.1126/scisignal.abb4324
van der Vlist, Michiel, et al. "Signaling by the inhibitory receptor CD200R is rewired by type I interferon." Science signaling vol. 14,704 (2021): eabb4324. doi: https://doi.org/10.1126/scisignal.abb4324
van der Vlist M, Ramos MIP, van den Hoogen LL, Hiddingh S, Timmerman LM, de Hond TAP, Kaan ED, van der Kroef M, Lebbink RJ, Peters FMA, Khoury-Hanold W, Fritsch-Stork R, Radstake TRDJ, Meyaard L. Signaling by the inhibitory receptor CD200R is rewired by type I interferon. Sci Signal. 2021 Oct 12;14(704):eabb4324. doi: 10.1126/scisignal.abb4324. Epub 2021 Oct 12. PMID: 34637328.
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Sci Signal. 2021 Oct 12;14(704):eabb4324. doi: 10.1126/scisignal.abb4324. Epub 2021 Oct 12.

Signaling by the inhibitory receptor CD200R is rewired by type I interferon.

Science signaling

Michiel van der Vlist, M Inês Pascoal Ramos, Lucas L van den Hoogen, Sanne Hiddingh, Laura M Timmerman, Titus A P de Hond, Ellen D Kaan, Maarten van der Kroef, Robert Jan Lebbink, Florence M A Peters, William Khoury-Hanold, Ruth Fritsch-Stork, Timothy R D J Radstake, Linde Meyaard

Affiliations

  1. Center for Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
  2. Oncode Institute, Utrecht, Netherlands.
  3. Center for Translational Immunology, Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
  4. Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
  5. Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

PMID: 34637328 DOI: 10.1126/scisignal.abb4324

Abstract

CD200 receptor 1 (CD200R) is an inhibitory immunoreceptor that suppresses Toll-like receptor (TLR)–induced cytokine production through the adaptor protein Dok2 and the GTPase activating protein (GAP) p120-RasGAP, which can be cleaved during mild cellular stress. We found that in the presence of cleaved p120-RasGAP, CD200R lost its capacity to inhibit phosphorylation of ribosomal S6 protein (rpS6), suggesting the reduced activity of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, treatment of human peripheral blood mononuclear cells (PBMC) with interferon-α (IFN-α) resulted in increased amounts of cleaved p120-RasGAP. Upon pretreatment of cells with increasing concentrations of IFN-α, CD200R switched from inhibiting to potentiating the TLR7- and TLR8-induced expression of the gene encoding IFN-γ, a cytokine that is important for innate and adaptive immunity and is implicated in systemic lupus erythematosus (SLE) pathogenesis. PBMC from patients with SLE, a prototypic type I IFN disease, had an increased abundance of cleaved p120-RasGAP compared to that in cells from healthy controls. In a subset of SLE patients, CD200R stopped functioning as an inhibitory receptor or potentiated TLR-induced IFNG mRNA expression. Thus, our data suggest that type I IFN rewires CD200R signaling to be proinflammatory, which could contribute to the perpetuation of inflammation in patients with SLE.

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