PMID- 35196494 OWN - NLM STAT- MEDLINE DCOM- 20220316 LR - 20240214 IS - 2211-1247 (Electronic) VI - 38 IP - 8 DP - 2022 Feb 22 TI - JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1-mediated regulatory T cell induction. PG - 110420 LID - S2211-1247(22)00144-9 [pii] LID - 10.1016/j.celrep.2022.110420 [doi] AB - 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-gamma-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. CI - Copyright (c) 2022 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Vogel, Andrea AU - Vogel A AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Martin, Katharina AU - Martin K AD - St. Anna Children's Cancer Research Institute, Vienna, Austria. FAU - Soukup, Klara AU - Soukup K AD - St. Anna Children's Cancer Research Institute, Vienna, Austria. FAU - Halfmann, Angela AU - Halfmann A AD - St. Anna Children's Cancer Research Institute, Vienna, Austria. FAU - Kerndl, Martina AU - Kerndl M AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Brunner, Julia S AU - Brunner JS AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Hofmann, Melanie AU - Hofmann M AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Oberbichler, Laura AU - Oberbichler L AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Korosec, Ana AU - Korosec A AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Kuttke, Mario AU - Kuttke M AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Datler, Hannes AU - Datler H AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Kieler, Markus AU - Kieler M AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Musiejovsky, Laszlo AU - Musiejovsky L AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. FAU - Dohnal, Alexander AU - Dohnal A AD - St. Anna Children's Cancer Research Institute, Vienna, Austria. Electronic address: alexander.dohnal@apeiron-biologics.com. FAU - Sharif, Omar AU - Sharif O AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. Electronic address: omar.sharif@meduniwien.ac.at. FAU - Schabbauer, Gernot AU - Schabbauer G AD - Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria. Electronic address: gernot.schabbauer@meduniwien.ac.at. LA - eng GR - P 30026/FWF_/Austrian Science Fund FWF/Austria GR - P 31568/FWF_/Austrian Science Fund FWF/Austria PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell Rep JT - Cell reports JID - 101573691 RN - 0 (B7-H1 Antigen) RN - 0 (Cd274 protein, mouse) RN - EC 2.7.10.2 (Jak1 protein, mouse) RN - EC 2.7.10.2 (Janus Kinase 1) SB - IM MH - Animals MH - Autoimmunity MH - *B7-H1 Antigen/immunology/metabolism MH - Dendritic Cells/metabolism MH - *Encephalomyelitis, Autoimmune, Experimental MH - Immune Tolerance MH - *Janus Kinase 1/immunology/metabolism MH - Mice MH - Peripheral Tolerance MH - *T-Lymphocytes, Regulatory OTO - NOTNLM OT - JAK1 OT - autoimmunity OT - dendritic cells OT - peripheral tolerance OT - regulatory T cells COIS- Declaration of interests The authors declare no competing interests. EDAT- 2022/02/24 06:00 MHDA- 2022/03/17 06:00 CRDT- 2022/02/23 20:08 PHST- 2021/05/11 00:00 [received] PHST- 2021/12/17 00:00 [revised] PHST- 2022/02/01 00:00 [accepted] PHST- 2022/02/23 20:08 [entrez] PHST- 2022/02/24 06:00 [pubmed] PHST- 2022/03/17 06:00 [medline] AID - S2211-1247(22)00144-9 [pii] AID - 10.1016/j.celrep.2022.110420 [doi] PST - ppublish SO - Cell Rep. 2022 Feb 22;38(8):110420. doi: 10.1016/j.celrep.2022.110420.