Galectin-9-Mediated Protection from Allo-Specific T Cells as a Mechanism of Immune Privilege of Corneal Allografts

Shimmura-Tomita, Machiko; Wang, Mingcong; Taniguchi, Hiroko; Akiba, Hisaya; Yagita, Hideo; Hori, Junko

doi:10.1371/journal.pone.0063620

Cited by 38 publications

(38 citation statements)

References 45 publications

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“…We now show that treatment with rGal-9 activated TIM-3 expression, diminished IR-triggered TLR4 activation and mitigated proinflammatory cytokine programs, ultimately leading to OLT cytoprotection. These beneficial effects are in agreement with the ability of Gal-9 to ameliorate diet-induced liver steatosis by modulating NKT cell function (31); prolong survival of fully allogeneic cardiac allografts by suppressing Th1/Th17 immune responses (32); or protect corneal allografts from destruction by allo-reactive T cells (33). …”

Section: Discussionsupporting

confidence: 71%

Negative CD4 + TIM-3 Signaling Confers Resistance Against Cold Preservation Damage in Mouse Liver Transplantation

Liu

Zhang

et al. 2015

American Journal of Transplantation

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Ischemia-reperfusion injury (IRI), an innate immunity-driven local inflammation, remains the major problem in clinical organ transplantation. T cell immunoglobulin and mucin domain (TIM-3) – Galectin-9 (Gal-9) signaling regulates CD4+ Th1 immune responses. Here, we explored TIM-3 – Gal-9 function in a clinically relevant murine model of hepatic cold storage and orthotopic liver transplantation (OLT). C57BL/6 livers, preserved for 20h at 4°C in UW solution, were transplanted to syngeneic mouse recipients. Up-regulation of TIM-3 on OLT-infiltrating activated CD4+ T cells was observed in the early IRI phase (1h). By 6h of reperfusion, OLTs in recipients treated with a blocking anti-TIM-3 Ab were characterized by: 1/ enhanced hepatocellular damage (sALT levels, liver Suzuki's histological score); 2/ polarized cell infiltrate towards Th1/Th17-type phenotype; 3/ depressed T cell exhaustion markers (PD-1, LAG3); and 4/ elevated neutrophil and macrophage infiltration/activation. In parallel studies, adoptive transfer of CD4+ T cells from naïve WT, but not from TIM-3 Tg donors, readily recreated OLT damage in otherwise IR-resistant RAG−/− test recipients. Furthermore, pre-treatment of mice with rGal-9 promoted hepatoprotection against preservation-association liver damage, accompanied by enhanced TIM-3 expression in OLTs. Thus, CD4+ T cell-dependent “negative” TIM-3 costimulation is essential for hepatic homeostasis and resistance against IR stress in OLTs.

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Section: Discussionsupporting

confidence: 71%

Negative CD4 + TIM-3 Signaling Confers Resistance Against Cold Preservation Damage in Mouse Liver Transplantation

Liu

Zhang

et al. 2015

American Journal of Transplantation

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“…On one hand, as proinflammatory factor, Gal-9 induces DC maturation to enhance Th1-type immunity [37]. On the other hand, Gal-9 may limit Th1 activation to protect against allo-specific T cell responses [38] and restrain allograft rejection [39]. Gal-9 may also serve as a key regulator in viral and inflammatory liver disease states [40,41].…”

Section: Discussionmentioning

confidence: 99%

Recipient T cell TIM-3 and hepatocyte galectin-9 signalling protects mouse liver transplants against ischemia-reperfusion injury

Liu

Zhang

et al. 2015

Journal of Hepatology

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Background & Aims By binding to T-cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, Galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 costimulation may rescue IR-stressed orthotopic liver transplants (OLT) from innate immunity-driven inflammation. Methods We used WT and TIM-3Tg mice (C57BL6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20h at 4°C in UW solution) and syngeneic OLT. Results OLTs in WT or TIM-3Tg->TIM-3Tg groups were resistant against IR- stress, evidenced by preserved hepatocellular function (sALT levels) and liver architecture (Suzuki’s score). In contrast, OLTs in WT or TIM-3Tg->WT groups were susceptible to IRI. TIM-3 induction in recipient circulating CD4+ T cells: 1/ depressed Tbet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in OLTs; 2/ promoted T cell exhaustion (PD-1, LAG-3) phenotype; and 3/ depressed neutrophil and macrophage infiltration/function in OLTs. In parallel studies, we have documented, for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in-vivo and in-vitro. Moreover, exogenous rGal-9 potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells. Conclusion Harnessing TIM-3–Gal-9 signaling at T cell–hepatocyte interface facilitates homeostasis in IR-stressed OLTs. Enhancing anti-oxidant hepatocyte Gal-9 potentiates liver IR-resistance. Negative regulation by recipient TIM-3+CD4+ cells provides evidence for cytoprotective functions of a discrete T cell subset, which should be spared when applying T cell-targeted immunosuppression in transplant recipients.

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“…250,271,272 Galectin family proteins have been implicated in a variety of ocular disorders, including inflammatory conditions of the conjunctivita and cornea, proliferative vitreoretinopathy, and diabetic retinopathy. [273][274][275][276][277][278] Numerous studies suggest that galectins are important in the maintenance of a healthy ocular surface at rest and after injury, 279,280 with galectins-1 and -9 specifically playing roles in the response to bacterial and viral pathogens that damage the corneal surface. [281][282][283] The healthy human lens 284 also expresses galectin-3, and a galectin-like molecule called GRIFIN (galectin-related inter-fiber protein).…”

Section: Figmentioning

confidence: 99%

Matricellular Proteins in the Trabecular Meshwork: Review and Update

Chatterjee

Villarreal

Rhee

2014

Journal of Ocular Pharmacology and Therapeutics

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Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, and intraocular pressure (IOP) is an important modifiable risk factor. IOP is a function of aqueous humor production and aqueous humor outflow, and it is thought that prolonged IOP elevation leads to optic nerve damage over time. Within the trabecular meshwork (TM), the eye's primary drainage system for aqueous humor, matricellular proteins generally allow cells to modulate their attachments with and alter the characteristics of their surrounding extracellular matrix (ECM). It is now well established that ECM turnover in the TM affects outflow facility, and matricellular proteins are emerging as significant players in IOP regulation. The formalized study of matricellular proteins in TM has gained increased attention. Secreted protein acidic and rich in cysteine (SPARC), myocilin, connective tissue growth factor (CTGF), and thrombospondin-1 and -2 (TSP-1 and -2) have been localized to the TM, and a growing body of evidence suggests that these matricellular proteins play an important role in IOP regulation and possibly the pathophysiology of POAG. As evidence continues to emerge, these proteins are now seen as potential therapeutic targets. Further study is warranted to assess their utility in treating glaucoma in humans.

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Galectin-9-Mediated Protection from Allo-Specific T Cells as a Mechanism of Immune Privilege of Corneal Allografts

Cited by 38 publications

References 45 publications

Negative CD4 + TIM-3 Signaling Confers Resistance Against Cold Preservation Damage in Mouse Liver Transplantation

Negative CD4 + TIM-3 Signaling Confers Resistance Against Cold Preservation Damage in Mouse Liver Transplantation

Recipient T cell TIM-3 and hepatocyte galectin-9 signalling protects mouse liver transplants against ischemia-reperfusion injury

Matricellular Proteins in the Trabecular Meshwork: Review and Update

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