Effect of TIM-3 Blockade on the Immunophenotype and Cytokine Profile of Murine Uterine NK Cells

Tripathi, Sudipta; Chabtini, Lola; Dakle, Pranal J.; Smith, Brian D.; Akiba, Hisaya; Yagita, Hideo; Guleria, Indira

doi:10.1371/journal.pone.0123439

Cited by 15 publications

(13 citation statements)

References 40 publications

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“…These cells possess a unique receptor phenotype with latent cytotoxicity and produce various cytokines that are essential for survival of the fetus. Previous studies have demonstrated that although uNK cells are beneficial in regulating normal pregnancy, they can be transformed into detrimental cells in response to bacterial and viral infections . The LPS‐treated pregnant mice exhibited a significant decrease in the number of uNK cells, as well as a significant increase in the number of uterine pro‐inflammatory neutrophils .…”

Section: Discussionmentioning

confidence: 91%

Endogenous TWEAK is critical for regulating the function of mouse uterine natural killer cells in an immunological model of pregnancy loss

Liu

Qin

et al. 2016

Immunology

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SummaryUterine natural killer (uNK) cells are the most abundant lymphocyte population in the feto-maternal interface during early gestation, and uNK cells play a significant role in the establishment and maintenance of pregnancy-related vascularization, as well as in tolerance to the fetus. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible molecule (Fn14), are involved in preventing local cytotoxicity and counterbalancing the cytotoxic function of uNK cells. Here, we studied the regulation of TWEAK/Fn14-mediated innate immunity in the uterus using a lipopolysaccharide (LPS)-induced model of abortion in pregnant mice. Specifically, we detected the expression of TWEAK and Fn14 in the uterus and in uNK cells following LPS treatment. Our results revealed that TWEAK and Fn14 are expressed by uNK cells in pregnant mice; in particular, it appears that the cytokine TWEAK is primarily derived from uNK cells. Interestingly, the down-regulation of TWEAK in uNK cells and the up-regulation of the Fn14 receptor in the uterus in LPS-treated mice may contribute to the disruption of decidual homeostasis by altering uNK cell cytotoxicity -ultimately leading to fetal rejection. In conclusion, the present study strongly suggests that the TWEAK-Fn14 axis in uNK cells is involved in maintaining the tolerance necessary for successful pregnancy.Keywords: fibroblast growth factor-inducible molecule; lipopolysaccharide-induced abortion; pregnant mice; tumour necrosis factor-like weak inducer of apoptosis; uterine natural killer cell cytotoxicity.

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Section: Discussionmentioning

confidence: 91%

Endogenous TWEAK is critical for regulating the function of mouse uterine natural killer cells in an immunological model of pregnancy loss

Liu

Qin

et al. 2016

Immunology

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“…TIM-3 blockade ex vivo increased cytotoxicity of NK cells from these patients, suggesting that TIM-3 inhibits NK function in chronic infection. Many other studies further support an inhibitory role of TIM-3 in NK cell-mediated immune responses [73,74,75,76]. In contrast, some studies demonstrated a positive role of TIM-3 in NK function [77].…”

Section: Targeting Tim-3 For Immunotherapy Of Cancermentioning

confidence: 92%

TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action

Yang

Turner

et al. 2017

IJMS

182

150

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Abstract:Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. Thus, targeting TIM-3 emerges as a promising approach for further improvement of current immunotherapy. Despite a large amount of experimental data showing an immune suppressive function of TIM-3 in vivo, the exact mechanisms are not well understood. To enable effective targeting of TIM-3 for tumor immunotherapy, further in-depth mechanistic studies are warranted. These studies will also provide much-needed insight for the rational design of novel combination therapy with other checkpoint blockers. In this review, we summarize key evidence supporting an immune regulatory role of TIM-3 and discuss possible mechanisms of action.

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“…uNK cells are the most plentiful granulated lymphocyte population in the maternal-feto interface during pregnancy (Gong et al, 2017). They secrete abundant cytokines and regulate trophoblast invasion, vascular remodeling, and placental development which are vital to success pregnancy (Tripathi et al, 2015;Gong et al, 2017). Our results showed that PFOA exposure significantly reduced the numbers of uNK cells, which is a plausible explanation for pregnancy loss.…”

Section: Discussionmentioning

confidence: 59%

Gestational Perfluorooctanoic Acid Exposure Inhibits Placental Development by Dysregulation of Labyrinth Vessels and uNK Cells and Apoptosis in Mice

et al. 2020

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Perfluorooctanoic acid (PFOA) is a widely used perfluorinated compound and known to cause developmental toxicity which includes the increase of resorbed embryo, decrease of fetal survival, and fetal growth retardation. Nevertheless, whether it is associated with alteration of placental development remains unknown. Pregnant mice were gavaged with 0, 2.5, 5, 10 mg PFOA /kg/day from pregnancy day (PD) 1 to PD 13. Results showed that PFOA exposure markedly decreased the placental weight and caused interstitial edema of placenta. Laminin staining indicated that blood sinusoids area was shrunken in placenta of PFOA-exposed mice. Furthermore, PFOA treatment significantly reduced numbers of uNK cells. Western blot analysis revealed that levels of Bax and cleavedcaspase 3 proteins were markedly up-regulated in PFOA-treated groups. In addition, TEM examination showed that PFOA treatment caused rupture of nuclear membrane and nuclear pyknosis and fragmentation. Thus, our results suggested that gestational PFOA exposure significantly inhibited development of early placenta through shrinkage of labyrinth vessels and downregulation of uNK cells and apoptosis induction, which may result in adverse gestational outcomes.

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Effect of TIM-3 Blockade on the Immunophenotype and Cytokine Profile of Murine Uterine NK Cells

Cited by 15 publications

References 40 publications

Endogenous TWEAK is critical for regulating the function of mouse uterine natural killer cells in an immunological model of pregnancy loss

Endogenous TWEAK is critical for regulating the function of mouse uterine natural killer cells in an immunological model of pregnancy loss

TIM-3 as a Target for Cancer Immunotherapy and Mechanisms of Action

Gestational Perfluorooctanoic Acid Exposure Inhibits Placental Development by Dysregulation of Labyrinth Vessels and uNK Cells and Apoptosis in Mice

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