| First Author | Vogel A | Year | 2022 |
| Journal | Cell Rep | Volume | 38 |
| Issue | 8 | Pages | 110420 |
| PubMed ID | 35196494 | Mgi Jnum | J:328350 |
| Mgi Id | MGI:6881880 | Doi | 10.1016/j.celrep.2022.110420 |
| Citation | Vogel A, et al. (2022) JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1-mediated regulatory T cell induction. Cell Rep 38(8):110420 |
| abstractText | 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. |
