Ag and <scp>IL</scp>‐2 immune complexes efficiently expand <scp>A</scp>g‐specific <scp>T</scp>reg cells that migrate in response to chemokines and reduce localized immune responses

Hamano, Ryoko; Baba, Tomohisa; Sasaki, Soichiro; Tomaru, Utano; Ishizu, Akihiro; Kawano, Mitsuhiro; Yamagishi, Masakazu; Mukaida, Naofumi

doi:10.1002/eji.201343434

Cited by 13 publications

(12 citation statements)

References 43 publications

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“…It has been shown previously that injections of IL-2/JES6-1 in the presence of Ag lead to the migration of Ag-specific Tregs to the site of Ag localization (23). Moreover, a recent study reported that IL-2 is required to generate a population of induced memory Tregs upon immunization that are maintained for .40 d (48).…”

Section: Discussionmentioning

confidence: 97%

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In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Beidaq

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Hofmann

et al. 2016

The Journal of Immunology

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Contact hypersensitivity (CHS) of murine skin serves as a model of allergic contact dermatitis. Hapten-specific CD8 T cells and neutrophils represent the major effector cells driving this inflammatory reaction whereas Foxp3+ regulatory T cells (Tregs) control the severity of inflammation. However, whether in vivo expansion of endogenous Tregs can downregulate CHS-mediated inflammation remains to be elucidated. In this study, we addressed this issue by using injection of an IL-2/anti–IL-2 mAb JES6-1 complex (IL-2/JES6-1) as a means of Treg induction in 2,4,6-trinitrochlorobenzene–induced CHS. IL-2/JES6-1 injection before or after hapten sensitization led to a considerable reduction of skin inflammation, even when rechallenged up to 3 wk after the last treatment. Conversely, Treg depletion re-established the CHS response in IL-2/JES6-1–treated mice. IL-2/JES6-1 injection resulted in increased frequencies of natural and peripheral Tregs in spleen and draining lymph nodes (LNs), elevated IL-10 and TGF-β production by CD4 T cells, reduced CD86 expression by dendritic cells, and led to lower numbers of hapten-specific IFN-γ–producing CD8 T effector cells in LNs. Neutrophil and CD8 T cell infiltration was reduced in inflamed ear tissue, whereas CTLA-4+Foxp3+ Treg frequencies were augmented. Adoptive transfer of LN cells of sensitized mice into recipients treated with IL-2/JES6-1 showed impaired CHS. Our results show that in vivo Treg expansion results in a prolonged CHS suppression, a sustained reduction of hapten-specific CD8 T cells, and a decrease in effector cell influx in inflamed tissue.

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Section: Discussionmentioning

confidence: 97%

“…In vivo administration of exogenous IL-2 complexed with mAbs of the anti-IL-2 clone JES6-1 induces a systemic and selective expansion of Foxp3 + Tregs (19,20). Treatment with IL-2/ JES6-1 was shown to suppress different inflammatory diseases (21)(22)(23)(24). Moreover, expansion of Tregs using IL-2/JES6-1 resulted in long-term allograft survival in mice (20).…”

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confidence: 99%

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

Beidaq

Link

Hofmann

et al. 2016

The Journal of Immunology

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“…During infection or inflammation, Treg cells can migrate from the blood to draining lymph nodes and inflamed tissues to inhibit the activation and proliferation of antigen-specific T-cells 1,2 . Tregs limit overwhelming immune response to pathogens via secretion of immunosuppressive cytokines such as IL-10 and TGF-β1.…”

Section: Introductionmentioning

confidence: 99%

CD69 enhances immunosuppressive function of regulatory T-cells and attenuates colitis by prompting IL-10 production

Yang

Zhang

et al. 2018

Cell Death Dis

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Foxp3+ regulatory T cells (Tregs) can inhibit immune responses and maintain immune tolerance by secreting immunosuppressive TGF-β1 and IL-10. However, the efficiency of Tregs become the major obstacle to their use for immunotherapy. In this study, we investigated the relevance of the C-type lectin receptor CD69 to the suppressive function. Compared to CD4+Foxp3+CD69− Tregs (CD69− Tregs), CD4+Foxp3+CD69+ Tregs (CD69+ Tregs) displayed stronger ability to maintain immune tolerance. CD69+ Tregs expressed higher levels of suppression-associated markers such as CTLA-4, ICOS, CD38 and GITR, and secreted higher levels of IL-10 but not TGF-β1. CD69+ Tregs from Il10+/+ rather than Il10−/− mice significantly inhibit the proliferation of CD4+ T cells. CD69 over-expression stimulated higher levels of IL-10 and c-Maf expression, which was compromised by silencing of STAT3 or STAT5. In addition, the direct interaction of STAT3 with the c-Maf promoter was detected in cells with CD69 over-expression. Moreover, adoptive transfer of CD69+ Tregs but not CD69−Tregs or CD69+ Tregs deficient in IL-10 dramatically prevented the development of inflammatory bowel disease (IBD) in mice. Taken together, CD69 is important to the suppressive function of Tregs by promoting IL-10 production. CD69+ Tregs have the potential to develop new therapeutic approach for autoimmune diseases like IBD.

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“…Several studies have reported that injection of low doses of monoclonal antibody (JES6‐1) targeting IL‐2/anti‐IL‐2 complexes (IL‐2c) selectively increased the number of Tregs in multiple organs, including the liver, spleen, and thymus . Furthermore, clinical trials have shown that IL‐2c is considered an effective treatment for autoimmunity, graft‐versus‐host disease, and inflammation . IL‐2c therapy could relieve the development of rheumatoid arthritis, type 1 diabetes, allergic airway disease, and lupus in mice, but the effect of this administration on Treg expansion in TRALI models is unclear.…”

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confidence: 99%

Preventing murine transfusion‐related acute lung injury by expansion of CD4⁺CD25⁺FoxP3⁺ Tregs using IL‐2/anti‐IL‐2 complexes

Kong

et al. 2018

Transfusion

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BACKGROUND: Transfusion-related acute lung injury (TRALI) is one of the most serious adverse events following transfusion, and there is no specific treatment in clinical practice. However, regulatory T cells (Tregs) have been suggested to play a potential role in the treatment of TRALI. This study investigated whether interleukin (IL)-2 or IL-2/anti-IL-2 complexes (IL-2c), which are mediators of Treg expansion, can modulate the severity of antibody-mediated TRALI in vivo. STUDY DESIGN AND METHODS:This study utilized a mouse model of the "two-hit" mechanism: BALB/c mice were primed with lipopolysaccharide (LPS) as the first hit, and then TRALI was induced by injecting major histocompatibility complex Class I antibodies. Mice injected with LPS only or LPS combined with isotype control antibodies served as controls. For the Tregdepleted groups, mice were infused with anti-mouse IL-2Rα first and then subjected to the same treatments as the TRALI group. Regarding IL-2-and IL-2c-treated mice, recombinant murine IL-2 or IL-2c was intraperitoneally administered to mice for 5 consecutive days before induction of the TRALI model. Samples were collected 2 hours after TRALI induction. RESULTS: Prophylactic administration of IL-2 or IL-2cto mice prevented the onset of edema, pulmonary protein levels, and proinflammatory factors that inhibited polymorphonuclear neutrophil aggregation in the lungs. Furthermore, the percentage of CD4 + CD25 + FoxP3 + Tregs was expanded in vivo using IL-2 and IL-2c compared to TRALI mice, as was confirmed through analysis of the spleen, blood, and lung. CONCLUSION:This study validates that the protective mechanisms against TRALI involve CD4 + CD25 + FoxP3 + Tregs, which can be expanded in vivo by IL-2 and IL-2c. This results in increased IL-10 levels and decreased IL-17A, thereby prophylactically preventing antibodymediated murine TRALI. ABBREVIATIONS: BALF = bronchoalveolar lavage fluid; HNA = human neutrophil antigen; IL = interleukin; IL-2c = IL-2/anti-IL-2 complexes; LPS = lipopolysaccharide; MPO = myeloperoxidase; MHC = major histocompatibility complex; Th17 = T helper 17; TRALI = transfusion-related acute lung injury; Tregs = regulatory T cells; W/D = wet-to-dry. From the

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Ag and IL‐2 immune complexes efficiently expand Ag‐specific Treg cells that migrate in response to chemokines and reduce localized immune responses

Cited by 13 publications

References 43 publications

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

CD69 enhances immunosuppressive function of regulatory T-cells and attenuates colitis by prompting IL-10 production

Preventing murine transfusion‐related acute lung injury by expansion of CD4⁺CD25⁺FoxP3⁺ Tregs using IL‐2/anti‐IL‐2 complexes

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Ag and IL‐2 immune complexes efficiently expand Ag‐specific Treg cells that migrate in response to chemokines and reduce localized immune responses

Cited by 13 publications

References 43 publications

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

In Vivo Expansion of Endogenous Regulatory T Cell Populations Induces Long-Term Suppression of Contact Hypersensitivity

CD69 enhances immunosuppressive function of regulatory T-cells and attenuates colitis by prompting IL-10 production

Preventing murine transfusion‐related acute lung injury by expansion of CD4+CD25+FoxP3+ Tregs using IL‐2/anti‐IL‐2 complexes

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Preventing murine transfusion‐related acute lung injury by expansion of CD4⁺CD25⁺FoxP3⁺ Tregs using IL‐2/anti‐IL‐2 complexes