IL-27 targets Foxp3+ Tregs to mediate antiinflammatory functions during experimental allergic airway inflammation

Nguyen, Quan; Jang, Eue Soon; Le, Hongnga T.; Kim, Sohee; Kim, DongKyun; Dvorina, Nina; Aronica, Mark A.; Baldwin, William M.; Asosingh, Kewal; Comhair, Suzy; Min, Booki

doi:10.1172/jci.insight.123216

Cited by 38 publications

(46 citation statements)

References 65 publications

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“…Previous studies have associated IL-27 effect on regulatory T lymphocytes (Tregs) with both pro-and anti-inflammatory roles. The IL-27 signaling might contribute to their suppressive activities via STAT1-dependent manner 32,33 or by attenuating the Th17-mediated inflammation as shown in an autoimmune model of experimental autoimmune encephalomyelitis 12 . On the other hand, Bin Dhuban et al showed that IL-27 impairs the suppressive capacity of human Treg via the gp130 receptor subunit 34 .…”

Section: Discussionmentioning

confidence: 99%

Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Paračková

Vrabcová

Zentsová

et al. 2020

Sci Rep

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Interleukin 27 (IL-27), a member of the IL-12 family, is important for T cell differentiation; however, little is known about its effect on dendritic cells (DCs). IL-27 can activate multiple signaling cascades, including the JAK/STAT pathway, and depending on the setting it can both promote and antagonize inflammatory responses. An anti-inflammatory function of IL-27 has been reported in several autoimmune diseases; however, in type 1 diabetes (T1D), an autoimmune disease where autoreactive cytotoxic T cells attack insulin-producing beta cells, IL-27 has been shown to have a dual role and contradictory effects. Here, we show impaired IL-27 signaling in a large cohort of T1D patients (n = 51) compared to age-and gender-matched healthy donors. Increased expression of the IL-27 receptor subunit IL-27Ralpha mRNA in purified myeloid DCs (mDCs), detected by gene expression microarrays was mirrored by enhanced signal transduction in T1D mDCs in response to IL-27 stimulation. Higher STAT phosphorylation in T1D patients was also accompanied by elevated expression of the inhibitory molecules PD-L1, PD-L2 and PD-1, which may suggest not only immunomodulatory mechanisms of IL-27 in T1D but also a compensatory effort of T1D dendritic cells against the ongoing inflammation.

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Section: Discussionmentioning

confidence: 99%

Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Paračková

Vrabcová

Zentsová

et al. 2020

Sci Rep

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“…However, it is equally possible that IL-27 receptor signaling in donor T cells may be required to generate Tr1 cells that inhibit aGVHD as reported by Zhang et al (22). Of note, IL-27 is capable of targeting multiple cell types including Tregs and conventional T cells; however, the IL-27 blockadedependent protection was found to be Treg-dependent (25)(26)(27).…”

Section: Discussionmentioning

confidence: 91%

“…In the context of GvHD, the level of endogenous IL-27 is elevated in recipient serum, which in turn inhibits Treg reconstitution and facilitates GvHD development (25). IL-27 plays a key role in regulating Foxp3 + Treg functions in chronic inflammation including colitis, allergic airway inflammation, autoimmunity, and cancers (24,(26)(27)(28)(29). These results suggest that IL-27mediated regulation of Treg functions may be a tool to mediate inflammation.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-27 Enforces Regulatory T Cell Functions to Prevent Graft-versus-Host Disease

Keslar

Nguyen

et al. 2020

Front. Immunol.

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Graft-versus-host disease (GvHD) remains a significant complication of allogeneic hematopoietic cell transplantation (HCT), associated with significant morbidity and mortality. GvHD is characterized by dysregulated immune responses and resulting tissue damage of target organs. Recent investigations have focused on Foxp3 + regulatory T cells (Tregs) as a therapeutic tool, based on its regulatory functions in GvHD pathogenesis and their instrumental role in mitigating GvHD severity while preserving graft-versus-leukemia (GvL) activity. There are several challenges to its clinical application, including their paucity, impaired suppressive activity, and instability in vivo. Herein, we report that IL-27 pre-stimulation enhances suppressive functions of both mouse and human Tregs. In a complete MHC mismatched murine bone marrow transplant model, IL-27 pre-stimulated polyclonal iTregs diminish acute (a)GvHD lethality, while preserving the GvL effect. Allo-antigen specificity further improves suppressive functions when combined with IL-27 pre-stimulation. In a xenogeneic (human to mouse) GvHD model, IL-27 pre-stimulated human iTregs are superior in protecting recipients from GvHD. Lastly, we compared gene expression profiles of circulating Tregs isolated from HCT recipients with and without aGvHD and found that Tregs from aGvHD patients express distinct gene signatures enriched in immune activation and inflammation. Therefore, these results highlight a novel function of IL-27 in enforcing Treg functions to prevent aGvHD mediated lethality, proposing the hypothesis that dysregulated Treg functions may account for the potential mechanisms underlying GvHD development.

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“…Cui proved IL‐27 signalling displayed anti‐inflammatory function on epithelial cells to decrease IL‐6, TNF‐α, GM‐CSF and CXCL1 expression 31 . In allergic airway inflammation, IL‐27 favoured Foxp3 + Treg function to inhibit T cell proliferation and finally attenuated inflammatory 32 . IL‐27 pathway promoted activated T cells to switch to Th2 polarization and up‐regulate IL‐10 secretion of CD4 + T cells 33 .…”

Section: Discussionmentioning

confidence: 98%

IL‐27 Rα⁺ cells promoted allorejection via enhancing STAT1/3/5 phosphorylation

Zhao

Liang

Chao

et al. 2020

J Cellular Molecular Medi

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Recently, emerging evidence strongly suggested that the activation of interleukin‐27 Receptor α (IL‐27Rα) could modulate different inflammatory diseases. However, whether IL‐27Rα affects allotransplantation rejection is not fully understood. Here, we investigated the role of IL‐27Rα on allorejection both in vivo and in vitro. The skin allotransplantation mice models were established, and the dynamic IL‐27Rα/IL‐27 expression was detected, and IL‐27Rα+ spleen cells adoptive transfer was performed. STAT1/3/5 phosphorylation, proliferation and apoptosis were investigated in mixed lymphocyte reaction (MLR) with recombinant IL‐27 (rIL‐27) stimulation. Finally, IFN‐γ/ IL‐10 in graft/serum from model mice was detected. Results showed higher IL‐27Rα/IL‐27 expression in allografted group compared that syngrafted group on day 10 (top point of allorejection). IL‐27Rα+ spleen cells accelerated allograft rejection in vivo. rIL‐27 significantly promoted proliferation, inhibited apoptosis and increased STAT1/3/5 phosphorylation of alloreactive splenocytes, and these effects of rIL‐27 could be almost totally blocked by JAK/ STAT inhibitor and anti‐IL‐27 p28 Ab. Finally, higher IL‐27Rα+IFN‐γ+ cells and lower IL‐27Rα+IL‐10+ cells within allografts, and high IFN‐γ/low IL‐10 in serum of allorejecting mice were detected. In conclusion, these data suggested that IL‐27Rα+ cells apparently promoted allograft rejection through enhancing alloreactive proliferation, inhibiting apoptosis and up‐regulating IFN‐γ via enhancing STAT pathway. Blocking IL‐27 pathway may favour to prevent allorejection, and IL‐27Rα may be as a high selective molecule for targeting diagnosis and therapy for allotransplantation rejection.

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IL-27 targets Foxp3+ Tregs to mediate antiinflammatory functions during experimental allergic airway inflammation

Cited by 38 publications

References 65 publications

Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Interleukin-27 Enforces Regulatory T Cell Functions to Prevent Graft-versus-Host Disease

IL‐27 Rα⁺ cells promoted allorejection via enhancing STAT1/3/5 phosphorylation

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IL-27 targets Foxp3+ Tregs to mediate antiinflammatory functions during experimental allergic airway inflammation

Cited by 38 publications

References 65 publications

Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Enhanced STAT3 phosphorylation and PD-L1 expression in myeloid dendritic cells indicate impaired IL-27Ralpha signaling in type 1 diabetes

Interleukin-27 Enforces Regulatory T Cell Functions to Prevent Graft-versus-Host Disease

IL‐27 Rα+ cells promoted allorejection via enhancing STAT1/3/5 phosphorylation

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IL‐27 Rα⁺ cells promoted allorejection via enhancing STAT1/3/5 phosphorylation