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ACS Applied Polymer Materials

ACS Applied Polymer Materials

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JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1-mediated regulatory T?cell induction

Published:22 February 2022 DOI: 10.1016/j.celrep.2022.110420 PMID: 35196494
Andrea Vogel,?Katharina Martin,?Klara Soukup,?Angela Halfmann,?Martina Kerndl,?Julia S Brunner,?Melanie Hofmann,?Laura Oberbichler,?Ana Korosec,?Mario Kuttke,?Hannes Datler,?Markus Kieler,?Laszlo Musiejovsky,?Alexander Dohnal,?Omar Sharif,?Gernot Schabbauer

Abstract

Dendritic cells (DCs) induce peripheral T?cell tolerance, but cell-intrinsic signaling cascades governing their stable tolerogenesis remain poorly defined. Janus Kinase 1 (JAK1) transduces cytokine-receptor signaling, and JAK inhibitors (Jakinibs), including JAK1-specific filgotinib, break inflammatory cycles in autoimmunity. Here, we report in heterogeneous DC populations of multiple secondary lymphoid organs that JAK1 promotes peripheral T?cell tolerance during experimental autoimmune encephalomyelitis (EAE). Mice harboring DC-specific JAK1 deletion exhibit elevated peripheral CD4+ T?cell expansion, less regulatory T?cells (Tregs), and worse EAE outcomes, whereas adoptive DC transfer ameliorates EAE pathogenesis by inducing peripheral Tregs, programmed cell death ligand 1 (PD-L1) dependently. This tolerogenic program is substantially reduced upon the transfer of JAK1-deficient DCs. DC-intrinsic IFN-γ-JAK1-STAT1 signaling induces PD-L1, which is required for DCs to convert CD4+ T?cells into Tregs in?vitro and attenuated upon JAK1 deficiency and filgotinib treatment. Thus, DC-intrinsic JAK1 promotes peripheral tolerance, suggesting potential unwarranted DC-mediated effects of Jakinibs in autoimmune diseases.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Filgotinib 1206161-97-8 C21H23N5O3S 287 suppliers $13.00-$7020.00
Filgotinib 1206161-97-8 C21H23N5O3S 287 suppliers $13.00-$7020.00
Filgotinib 1206161-97-8 C21H23N5O3S 287 suppliers $13.00-$7020.00
Filgotinib 1206161-97-8 C21H23N5O3S 287 suppliers $13.00-$7020.00

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