Acute Lipopolysaccharide-Induced Inflammation Lowers IL-2R Signaling and the Proliferative Potential of Regulatory T Cells
Copyright © 2020 The Authors..
IL-2R signaling is essential for the development and homeostasis of CD4+Foxp3+ regulatory T cells (Tregs). Low-dose IL-2 is being advanced as a therapy for autoimmune diseases because of its ability to expand Tregs. Although Treg stability and function is diminished by chronic inflammation, the impact of inflammation on proximal IL-2R signaling and/or responsiveness to low-dose IL-2 is poorly understood. In this study, we show that acute inflammation induced by LPS, analogous to responses to acute bacterial infection, led to decreased endogenous STAT5 signaling and proliferative potential as measured by Ki67 in mouse Tregs. This impaired Treg activity was transient, did not lead to a reduction in Treg numbers or function, and was due to TLR signaling by non-Tregs. Although acute LPS induced high levels of IL-1 and IL-6, these cytokines did not solely mediate dysregulated Treg activity. Global gene expression analyses demonstrated that acute LPS-induced inflammation substantially and rapidly altered the Treg transcriptome. In the presence of an IL-2R agonist, the mouse IL-2/CD25 fusion protein (mIL-2/CD25), this type of inflammatory response tempered the transcription of IL-2R-dependent genes in vivo. Gene enrichment and pathway analyses are consistent with LPS attenuating mIL-2/CD25-dependent genes related to the cell cycle, DNA replication, and cholesterol biosynthesis while enhancing mRNAs that mediated Treg suppression in vivo. Acute LPS-induced inflammation diminished some responses by Tregs to mIL-2/CD25 treatment in vivo. Together, these results suggest a role for persistent IL-2R signaling in mitigating some but not all of the deleterious effects of inflammation on Treg proliferation while supporting their function.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
ImmunoHorizons - 4(2020), 12 vom: 17. Dez., Seite 809-824 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hsiung, Sunnie [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.11.2021 Date Revised 09.11.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.4049/immunohorizons.2000099 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM318997975 |
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| 520 | |a Copyright © 2020 The Authors. | ||
| 520 | |a IL-2R signaling is essential for the development and homeostasis of CD4+Foxp3+ regulatory T cells (Tregs). Low-dose IL-2 is being advanced as a therapy for autoimmune diseases because of its ability to expand Tregs. Although Treg stability and function is diminished by chronic inflammation, the impact of inflammation on proximal IL-2R signaling and/or responsiveness to low-dose IL-2 is poorly understood. In this study, we show that acute inflammation induced by LPS, analogous to responses to acute bacterial infection, led to decreased endogenous STAT5 signaling and proliferative potential as measured by Ki67 in mouse Tregs. This impaired Treg activity was transient, did not lead to a reduction in Treg numbers or function, and was due to TLR signaling by non-Tregs. Although acute LPS induced high levels of IL-1 and IL-6, these cytokines did not solely mediate dysregulated Treg activity. Global gene expression analyses demonstrated that acute LPS-induced inflammation substantially and rapidly altered the Treg transcriptome. In the presence of an IL-2R agonist, the mouse IL-2/CD25 fusion protein (mIL-2/CD25), this type of inflammatory response tempered the transcription of IL-2R-dependent genes in vivo. Gene enrichment and pathway analyses are consistent with LPS attenuating mIL-2/CD25-dependent genes related to the cell cycle, DNA replication, and cholesterol biosynthesis while enhancing mRNAs that mediated Treg suppression in vivo. Acute LPS-induced inflammation diminished some responses by Tregs to mIL-2/CD25 treatment in vivo. Together, these results suggest a role for persistent IL-2R signaling in mitigating some but not all of the deleterious effects of inflammation on Treg proliferation while supporting their function | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Il2ra protein, mouse |2 NLM | |
| 650 | 7 | |a Interleukin-2 Receptor alpha Subunit |2 NLM | |
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| 700 | 1 | |a Chen, Xi |e verfasserin |4 aut | |
| 700 | 1 | |a Savio, Alicia Santos |e verfasserin |4 aut | |
| 700 | 1 | |a Hernandez, Rosmely |e verfasserin |4 aut | |
| 700 | 1 | |a Malek, Thomas R |e verfasserin |4 aut | |
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