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Myeloid Cell–Intrinsic IRF5 Promotes T Cell Responses through Multiple Distinct Checkpoints In Vivo, and IRF5 Immune-Mediated Disease Risk Variants Modulate These Myeloid Cell Functions

Jie Yan, Matija Hedl and Clara Abraham
J Immunol July 20, 2020, ji1900743; DOI: https://doi.org/10.4049/jimmunol.1900743
Jie Yan
Department of Internal Medicine, Yale University, New Haven, CT 06520
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Matija Hedl
Department of Internal Medicine, Yale University, New Haven, CT 06520
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Clara Abraham
Department of Internal Medicine, Yale University, New Haven, CT 06520
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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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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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Myeloid Cell–Intrinsic IRF5 Promotes T Cell Responses through Multiple Distinct Checkpoints In Vivo, and IRF5 Immune-Mediated Disease Risk Variants Modulate These Myeloid Cell Functions
Jie Yan, Matija Hedl, Clara Abraham
The Journal of Immunology July 20, 2020, ji1900743; DOI: 10.4049/jimmunol.1900743

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Myeloid Cell–Intrinsic IRF5 Promotes T Cell Responses through Multiple Distinct Checkpoints In Vivo, and IRF5 Immune-Mediated Disease Risk Variants Modulate These Myeloid Cell Functions
Jie Yan, Matija Hedl, Clara Abraham
The Journal of Immunology July 20, 2020, ji1900743; DOI: 10.4049/jimmunol.1900743
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Print ISSN 0022-1767        Online ISSN 1550-6606