Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis

Seki, Masako; Oomizu, Souichi; Sakata, Kozue; Sakata, Atsuko; Arikawa, Tomohiro; Watanabe, Kota; Ito, Kanako; Takeshita, Kenjiro; Niki, Toshiro; Saita, Naoki; Nishi, Nozomu; Yamauchi, Akira; Katoh, Shigeki; Matsukawa, Akihiro; Kuchroo, Vijay K.; Hirashima, Mitsuomi

doi:10.1016/j.clim.2008.01.006

Cited by 412 publications

(462 citation statements)

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“…Recently, the suppressive effects of gal-9 have also been assessed in a mouse collagen-induced arthritis (CIA) model. Gal-9 ameliorates CIA by suppressing CD4 1 TIM-3 1 T cells and downregulating proinflammatory cytokines [30]. From another viewpoint, blocking the interaction between gal-9 and TIM-3 with anti-TIM-3 antibody reduces allergen-induced airway inflammation by skewing the Th2 response toward a Th1 type, suggesting an important role for TIM-3 in the regulation of the Th1/Th2 balance in the allergic disease [33].…”

Section: Discussionmentioning

confidence: 99%

“…Taken together, the effect of TIM-3ÀTIM-3L on the regulatory T-cell function is still unclear. Recently, Seki et al showed that gal-9 deficiency in C57BL/6J background reduces regulatory T-cell development [30], but detail mechanism(s) was/were not addressed. Therefore, there is no direct evidence supporting that gal-9 could alter the regulatory T-cell function.…”

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confidence: 99%

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Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

2009

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Galectin-9 (gal-9), widely expressed in many tissues, regulates Th1 cells and induces their apoptosis through its receptor, T-cell Ig mucin 3, which is mainly expressed on terminally differentiated Th1 cells. Type 1 diabetes is a Th1-dominant autoimmune disease that specifically destroys insulin-producing b cells. To suppress the Th1 immune response in the development of autoimmune diabetes, we overexpressed gal-9 in NOD mice by injection of a plasmid encoding gal-9. Mice treated with gal-9 plasmid were significantly protected from diabetes and showed less severe insulitis compared with controls. Flow cytometric analyses in NOD-T1/2 double transgenic mice showed that Th1-cell population in spleen, pancreatic lymph node and pancreas was markedly decreased in gal-9 plasmidtreated mice, indicating a negative regulatory role of gal-9 in the development of pathogenic Th1 cells. Splenocytes from gal-9 plasmid-treated mice were less responsive to mitogenic stimulation than splenocytes from the control group. However, adoptive transfer of splenocytes from gal-9-treated or control mice caused diabetes in NOD/SCID recipients with similar kinetics, suggesting that gal-9 treatment does not induce active tolerance in NOD mice. We conclude that gal-9 may downregulate Th1 immune response in NOD mice and could be used as a therapeutic target in autoimmune diabetes.Key words: Galectin-9 . Th1 . T-cell Ig mucin 3 . Type 1 diabetes IntroductionWhen CD4 1 Th cells interact with class II MHC-peptide complex and costimulatory molecules on APC, they differentiate into several effector subsets. There are two major Th subsets that have unique patterns of cytokine secretion and different functional properties. Th1 cells produce cytokines such as IFN-g, IL-2, TNF-a and lymphotoxin that are commonly associated with cellmediated immune responses against intracellular pathogens, delayed-type hypersensitivity and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines such as IL-4, IL-5, IL-10 and IL-13 that are crucial for controlling extracellular helminth infections and promoting atopic and allergic diseases [1,2].Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease that selectively destroys the insulin-producing b cells in the pancreas. NOD mice spontaneously develop autoimmune diabetes with immunopathological features resembling those of human disease and can be used as an animal model to study the pathogenesis of T1D. Previous studies have demonstrated that transfer of NOD CD4 1 T cells to immunodeficient NOD/SCID mice can induce diabetes in those recipients, indicating that CD4 1 T cells play an important role in the pathogenesis of diabetes [3,4] [12]. Previous approaches using TIM-3-Ig fusion protein to interrupt the interactions between TIM-3 and its ligand in vivo resulted in hyperproliferation of Th1 cells and release of Th1-related cytokines [13]. TIM-3 ligand was subsequently identified as galectin-9 (gal-9) [14], a b-galactoside binding lectin that belongs to a growing family of animal lectins, the...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

2009

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“…cDNA was synthesized from total RNA using RNase H À reverse transcriptase (Invitrogen) and oligo(dT) [12][13][14][15][16][17][18] (Invitrogen). Amplification of cDNA for Tim3-hIg was performed using primers TIM-3F, 5 0 -GCT AGC ATG TTT TCA GGT CTT ACC CTC AAC TGT G-3 0 , and HIgCR, 5 0 -CGG GAT CCT CAT TTA CCC TGC GAC AG-3 0 .…”

Section: Reverse Transcription (Rt)-pcrmentioning

confidence: 99%

“…Tim3 expressed by monocytes and dendritic cells facilitates phagocytosis of apoptotic cells and up-regulates cross-presentation of apoptotic cell-associated antigens through interaction with phosphatidylserine [12,14]. Galectin-9 induces the death of Th1 cells, which results in the suppression of both Th1 autoimmunity and the generation of Th17 cells [13,15]. Stimulation of Tim3 with an agonistic antibody promotes inflammation through the activation of innate immune cells [16].…”

Section: Introductionmentioning

confidence: 99%

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

Lee

Woo

Heo

et al. 2010

Biochemical and Biophysical Research Communications

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“…Similarly to gal-1, gal-9 down-regulates Th-1 and Th17 responses, and is involved in the suppression induced by CD4+ CD25+ regulatory T cells through its interaction with the Th-1-specific cell surface molecule TIM-3 [9,10]. Studies in models of inflammatory disease, such as complex immune-induced arthritis, allergic asthma and diabetes, support an anti-inflammatory role for gal-9 [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Psoriasis in humans is associated with down‐regulation of galectins in dendritic cells

Fuente

Pérez‐Gala

Bonay

et al. 2012

The Journal of Pathology

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2 ABSTRACT.We have investigated the expression and role of galectin-1 and other galectins in psoriasis and in the Th1/Th17 effector and dendritic cell responses associated with this chronic inflammatory skin condition. To determine differences between psoriasis patients and healthy donors, galectins expression was analyzed by RT-PCR assays in skin samples and specifically on epidermal and peripheral blood dendritic cells by immunofluorescence and flow cytometry.In skin of healthy donors galectins 1, 3 and 9 were expressed in a high proportion of Langerhans cells. Also, galectins were differentially expressed in peripheral blood dendritic cell subsets; galectin-1 and galectin-9 were highly expressed in peripheral myeloid dendritic cells compared with plasmacytoid dendritic cells. We found that non-lesional as well as lesional skin samples from psoriasis patients had low levels of galectin-1 at mRNA and protein level in parallel with low levels of IL-10 mRNA compared with skin from healthy patients. However, only lesional skin samples expressed high levels of

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Galectin-9 suppresses the generation of Th17, promotes the induction of regulatory T cells, and regulates experimental autoimmune arthritis

Cited by 412 publications

References 42 publications

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

Psoriasis in humans is associated with down‐regulation of galectins in dendritic cells

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