Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

Bobbala, Diwakar; Mayhue, Marian; Menéndez, Alfredo; Ilangumaran, Subburaj; Ramanathan, Sheela

doi:10.1038/cmi.2015.102

Cited by 15 publications

(18 citation statements)

References 38 publications

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“…The expression of CD122 is a major phenotypic marker of NKPs, which allows the cells to respond to IL-15 ( 124 , 125 ). IL-15 has a special manner of transducing its signals through trans-presentation, whereby the IL-15-producing cells support IL-15 by binding IL-15Rα, and then present it to activate neighboring cells expressing CD122/CD132 ( 126 – 130 ). Enlightened by these findings, researchers have designed NK cells expressing membrane-bound IL-15 that have autonomous growth and increased cytotoxicity toward tumor cells, which can help to enhance the antitumor effects of NK cells and avoid the side effects of cytokine administration ( 131 ).…”

Section: Regulation Of Nk Cell Development By Cytokinesmentioning

confidence: 99%

Developmental and Functional Control of Natural Killer Cells by Cytokines

2017

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Natural killer (NK) cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL), kit ligand (KL), interleukin (IL)-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment.

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Section: Regulation Of Nk Cell Development By Cytokinesmentioning

confidence: 99%

Developmental and Functional Control of Natural Killer Cells by Cytokines

2017

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“…Thus, neutralization of IL-15 or blockade of IL-15 signaling may prevent inflammation and activate brown/beige function during nutrient excess. Our study suggests that IL-15 may be a therapeutic target not only in autoimmune type 1 diabetes [ 17 , 59 , 60 ], but also in obesity.…”

Section: Discussionmentioning

confidence: 91%

Deficiency of Interleukin-15 Confers Resistance to Obesity by Diminishing Inflammation and Enhancing the Thermogenic Function of Adipose Tissues

et al. 2016

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ObjectiveIL-15 is an inflammatory cytokine secreted by many cell types. IL-15 is also produced during physical exercise by skeletal muscle and has been reported to reduce weight gain in mice. Contrarily, our findings on IL-15 knockout (KO) mice indicate that IL-15 promotes obesity. The aim of this study is to investigate the mechanisms underlying the pro-obesity role of IL-15 in adipose tissues.MethodsControl and IL-15 KO mice were maintained on high fat diet (HFD) or normal control diet. After 16 weeks, body weight, adipose tissue and skeletal mass, serum lipid levels and gene/protein expression in the adipose tissues were evaluated. The effect of IL-15 on thermogenesis and oxygen consumption was also studied in primary cultures of adipocytes differentiated from mouse preadipocyte and human stem cells.ResultsOur results show that IL-15 deficiency prevents diet-induced weight gain and accumulation of lipids in visceral and subcutaneous white and brown adipose tissues. Gene expression analysis also revealed elevated expression of genes associated with adaptive thermogenesis in the brown and subcutaneous adipose tissues of IL-15 KO mice. Accordingly, oxygen consumption was increased in the brown adipocytes from IL-15 KO mice. In addition, IL-15 KO mice showed decreased expression of pro-inflammatory mediators in their adipose tissues.ConclusionsAbsence of IL-15 results in decreased accumulation of fat in the white adipose tissues and increased lipid utilization via adaptive thermogenesis. IL-15 also promotes inflammation in adipose tissues that could sustain chronic inflammation leading to obesity-associated metabolic syndrome.

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“…Following juvenile BPA exposure, the cytokine/chemokines that were still altered on PND134 included increased levels of LIX, suggesting a pro-inflammation, while increased GCSF and IL-5, and decreased IL-15 and EOTAXIN are more supportive of an antiinflammatory shift (Bobbala et al 2017;Chao et al 2014;Haller et al 2016;Tuller et al 2013;Zhang et al 2014). In terms of immune changes, both B220 + CD40L − B cells and CD4 + CD8 + T cells, which can have either autoreactive or suppressive roles in immunity (Overgaard et al 2015), were decreased after juvenile BPA exposure.…”

Section: Discussionmentioning

confidence: 99%

Bisphenol A alteration of type 1 diabetes in non-obese diabetic (NOD) female mice is dependent on window of exposure

Huang

Nagy

et al. 2019

Arch Toxicol

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Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic β-cell destruction can be mediated by dysbiosis, infiltration of pro-inflammatory immune cells, and cytokines/chemokines. Exposure to bisphenol A (BPA), an endocrine disruptor (ED), can lead to aberrant immunity and gut microbiota. We determined whether BPA had age-dependent effects on T1D by modulating immune homeostasis following various windows of exposure in non-obese diabetic (NOD) mice. Juvenile NOD females were orally exposed to 0 or 30 μg BPA/kg BW from postnatal day (PND) 28 to PND56. Adult NOD females were exposed to 0 or 300 μg BPA/kg BW. Female and male NOD offspring were exposed to 0 or 300 μg BPA/kg BW perinatally from gestation day 5 to PND28 by dosing the dams. It was found that BPA increased T1D risk in juvenile females with gut microbiota shifted towards pro-inflammation (e.g. increased Jeotgalicoccus). In agreement with our previous study, adult females had a trend of increased T1D and a general increase in immune responses. However, female offspring had a reduced T1D development. Consistently, female offspring had a shift towards anti-inflammation (e.g. decreased pro-inflammatory F4/80 + Gr1 + cells). In contrast, BPA had minimal effects on immunity and T1D in male offspring. Thus, it was concluded that BPA had age-and sex-dependent effects on T1D with the alteration of gut microbiota and inflammation being the primary mechanisms for T1D exacerbation in juvenile exposure and decreases of inflammation being responsible for attenuated T1D in perinatally exposed females.

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Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

Cited by 15 publications

References 38 publications

Developmental and Functional Control of Natural Killer Cells by Cytokines

Developmental and Functional Control of Natural Killer Cells by Cytokines

Deficiency of Interleukin-15 Confers Resistance to Obesity by Diminishing Inflammation and Enhancing the Thermogenic Function of Adipose Tissues

Bisphenol A alteration of type 1 diabetes in non-obese diabetic (NOD) female mice is dependent on window of exposure

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