Key Points
Myeloid cell–intrinsic IRF5 regulates chemokine-dependent T cell migration.
Myeloid cell IRF5 regulates key checkpoints in T cell activation/differentiation.
IRF5 risk variants modulate myeloid cell–dependent T cell–conditioning outcomes.
Abstract
Common IRF5 genetic risk variants associated with multiple immune-mediated diseases are a major determinant of interindividual variability in pattern-recognition receptor (PRR)–induced cytokines in myeloid cells. However, how myeloid cell–intrinsic IRF5 regulates the multiple distinct checkpoints mediating T cell outcomes in vivo and IRF5-dependent mechanisms contributing to these distinct checkpoints are not well defined. Using an in vivo Ag-specific adoptive T cell transfer approach into Irf5−/− mice, we found that T cell–extrinsic IRF5 regulated T cell outcomes at multiple critical checkpoints, including chemokine-mediated T cell trafficking into lymph nodes and PDK1-dependent soluble Ag uptake, costimulatory molecule upregulation, and secretion of Th1 (IL-12)– and Th17 (IL-23, IL-1β, and IL-6)–conditioning cytokines by myeloid cells, which then cross-regulated Th2 and regulatory T cells. IRF5 was required for PRR-induced MAPK and NF-κB activation, which, in turn, regulated these key outcomes in myeloid cells. Importantly, mice with IRF5 deleted from myeloid cells demonstrated T cell outcomes similar to those observed in Irf5−/− mice. Complementation of IL-12 and IL-23 was able to restore T cell differentiation both in vitro and in vivo in the context of myeloid cell–deficient IRF5. Finally, human monocyte-derived dendritic cells from IRF5 disease-associated genetic risk carriers leading to increased IRF5 expression demonstrated increased Ag uptake and increased PRR-induced costimulatory molecule expression and chemokine and cytokine secretion compared with monocyte-derived dendritic cells from low-expressing IRF5 genetic variant carriers. These data establish that myeloid cell–intrinsic IRF5 regulates multiple distinct checkpoints in T cell activation and differentiation and that these are modulated by IRF5 disease risk variants.
Footnotes
This work was supported by National Institutes of Health R01AI120369 and R01DK099097 and the Crohn’s and Colitis Foundation.
The online version of this article contains supplemental material.
- Received July 1, 2019.
- Accepted June 16, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.
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