Journal
IMMUNITY
Volume 54, Issue 2, Pages 235-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2020.12.001
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Funding
- NIH [R01AI137057, DP2DA042422, R01AI124378, R01AI153098, DK068181, AI113333, DK043351, GM138599]
- Harvard University Milton Award
- Gilead Research Scholars Program
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The study identified conventional dendritic cells as a major source of circulating sIL-6R, which regulates IL-6 signaling through a T cell-independent pathway, providing important insights into modulating pro-inflammatory immune reactions.
The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.
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