Cutting Edge: IL-27 Attenuates Autoimmune Neuroinflammation via Regulatory T Cell/Lag3–Dependent but IL-10–Independent Mechanisms In Vivo

Kim, Dongkyun; Le, Hongnga T.; Nguyen, Quan; Kim, Sohee; Lee, Juyeun; Min, Booki

doi:10.4049/jimmunol.1800898

Cited by 30 publications

(40 citation statements)

References 18 publications

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“…In myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) model, Kadowaki et al 88 demonstrated that LAG-3 blockade abrogated the anti-inflammatory effect of gut environment-induced intraepithelial MOG-specific CD4 + T cells. Kim et al 89 also reported that the ability of in vitro-generated induced T reg (iT reg ) cells to rescue T reg -depleted mice from lethal EAE was dependent on the expression of LAG-3 on the iT reg cells.…”

Section: Lag-3 In Autoimmunitymentioning

confidence: 99%

LAG-3: from molecular functions to clinical applications

Maruhashi

Sugiura

Okazaki

et al. 2020

J Immunother Cancer

316

222

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To prevent the destruction of tissues owing to excessive and/or inappropriate immune responses, immune cells are under strict check by various regulatory mechanisms at multiple points. Inhibitory coreceptors, including programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), serve as critical checkpoints in restricting immune responses against self-tissues and tumor cells. Immune checkpoint inhibitors that block PD-1 and CTLA-4 pathways significantly improved the outcomes of patients with diverse cancer types and have revolutionized cancer treatment. However, response rates to such therapies are rather limited, and immune-related adverse events are also observed in a substantial patient population, leading to the urgent need for novel therapeutics with higher efficacy and lower toxicity. In addition to PD-1 and CTLA-4, a variety of stimulatory and inhibitory coreceptors are involved in the regulation of T cell activation. Such coreceptors are listed as potential drug targets, and the competition to develop novel immunotherapies targeting these coreceptors has been very fierce. Among such coreceptors, lymphocyte activation gene-3 (LAG-3) is expected as the foremost target next to PD-1 in the development of cancer therapy, and multiple clinical trials testing the efficacy of LAG-3-targeted therapy are underway. LAG-3 is a type I transmembrane protein with structural similarities to CD4. Accumulating evidence indicates that LAG-3 is an inhibitory coreceptor and plays pivotal roles in autoimmunity, tumor immunity, and anti-infection immunity. In this review, we summarize the current understanding of LAG-3, ranging from its discovery to clinical application.

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Section: Lag-3 In Autoimmunitymentioning

confidence: 99%

LAG-3: from molecular functions to clinical applications

Maruhashi

Sugiura

Okazaki

et al. 2020

J Immunother Cancer

316

222

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“…In support, we recently demonstrated that IL-27 signaling in Tregs is indispensable in mediating Treg function to suppress chronic inflammation, because systemic IL-27 administration was unable to reverse autoimmune and allergic inflammation in the absence of Tregs or Treg expression of the IL-27R (27,28). IL-27 is known to antagonize iTreg differentiation if added to naive CD4 T cell activation (23).…”

Section: Discussionmentioning

confidence: 87%

“…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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“…Cytokines made in the gastric mucosa during inflammation likely contribute to the development of preneoplastic changes such as atrophy, hyperplasia, metaplasia, and dysplasia that predispose to carcinogenesis. IL27 plays a protective role in other inflammatory diseases, 20 , 33 and recently was detected at high levels in human patients with chronic gastritis. 24 We hypothesized that IL27 also may play a protective role during gastritis.…”

Section: Resultsmentioning

confidence: 99%

“…The rIL27 dose was based on previous studies that successfully had prevented other inflammatory diseases using mini osmotic pumps loaded with rIL27. 20 , 33 Mice were killed 4 weeks after implantation and the severity of gastritis pathology and metaplasia development was assessed using the pathologic and immunofluorescent methods described previously. The stomachs of rIL27-treated mice were much healthier than those from untreated mice.…”

Section: Resultsmentioning

confidence: 99%

Interleukin 27 Protects From Gastric Atrophy and Metaplasia During Chronic Autoimmune Gastritis

Bockerstett

Petersen

Noto

et al. 2020

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. Methods We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23x Ebi3 -/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues. Results We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. Conclusions In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell–mediated inflammation in the gastric mucosa.

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Cutting Edge: IL-27 Attenuates Autoimmune Neuroinflammation via Regulatory T Cell/Lag3–Dependent but IL-10–Independent Mechanisms In Vivo

Cited by 30 publications

References 18 publications

LAG-3: from molecular functions to clinical applications

LAG-3: from molecular functions to clinical applications

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

Interleukin 27 Protects From Gastric Atrophy and Metaplasia During Chronic Autoimmune Gastritis

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