Aberrant Presentation of Self-Lipids by Autoimmune B Cells Depletes Peripheral iNKT Cells

Tan, Andy Hee-Meng; Chong, William Pooi-Kat; Ng, Siew Bee; Basri, Nurhidayah; Xu, Shengli; Lam, Kong-Peng

doi:10.1016/j.celrep.2014.08.043

Cited by 17 publications

(16 citation statements)

References 36 publications

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“…For example, the loss of CD1d expression on B cells, following Epstein–Barr virus infection, results in severe attenuation of iNKT cell functions 49 . Data from our laboratory and confirmed by other groups 1 , 50 suggested that aberrant CD1d expression by B cells is associated with iNKT cell functional defect observed in SLE patients. These findings suggest that CD1d-mediated B-iNKT cell cross talk may be important in iNKT cell homeostasis and for regulation of suppression.…”

Section: Discussionsupporting

confidence: 83%

CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells

et al. 2018

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Regulatory B cells (Breg) express high levels of CD1d that presents lipid antigens to invariant natural killer T (iNKT) cells. The function of CD1d in Breg biology and iNKT cell activity during inflammation remains unclear. Here we show, using chimeric mice, cell depletion and adoptive cell transfer, that CD1d–lipid presentation by Bregs induces iNKT cells to secrete interferon (IFN)-γ to contribute, partially, to the downregulation of T helper (Th)1 and Th17-adaptive immune responses and ameliorate experimental arthritis. Mice lacking CD1d-expressing B cells develop exacerbated disease compared to wild-type mice, and fail to respond to treatment with the prototypical iNKT cell agonist α-galactosylceramide. The absence of lipid presentation by B cells alters iNKT cell activation with disruption of metabolism regulation and cytokine responses. Thus, we identify a mechanism by which Bregs restrain excessive inflammation via lipid presentation.

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Section: Discussionsupporting

confidence: 83%

CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells

et al. 2018

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“…Mouse liver tissue was harvested, flash frozen in liquid nitrogen and stored at −80 °C prior to extraction. Subsequently, 50 mg of tissue was homogenized at 4 °C and metabolites extracted as described previously 44 using a mixture of cold methanol, tricine and chloroform. The lipid fraction (chloroform layer) was then collected and stored at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis

Huo

Ma²,

Liu

et al. 2016

Cell Death Dis

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Altered hepatic lipogenesis is associated with metabolic diseases such as obesity and hepatosteatosis. Insulin resistance and compensatory hyperinsulinaemia are key drivers of these metabolic imbalances. Fas apoptosis inhibitory molecule (FAIM), a ubiquitously expressed antiapoptotic protein, functions as a mediator of Akt signalling. Since Akt acts at a nodal point in insulin signalling, we hypothesize that FAIM may be involved in energy metabolism. In the current study, C57BL/6 wild-type (WT) and FAIM-knockout (FAIM-KO) male mice were fed with normal chow diet and body weight changes were monitored. Energy expenditure, substrate utilization and physical activities were analysed using a metabolic cage. Liver, pancreas and adipose tissue were subjected to histological examination. Serum glucose and insulin levels and lipid profiles were determined by biochemical assays. Changes in components of the insulin signalling pathway in FAIM-KO mice were examined by immunoblots. We found that FAIM-KO mice developed spontaneous non-hyperphagic obesity accompanied by hepatosteatosis, adipocyte hypertrophy, dyslipidaemia, hyperglycaemia and hyperinsulinaemia. In FAIM-KO liver, lipogenesis was elevated as indicated by increased fatty acid synthesis and SREBP-1 and SREBP-2 activation. Notably, protein expression of insulin receptor beta was markedly reduced in insulin target organs of FAIM-KO mice. Akt phosphorylation was also lower in FAIM-KO liver and adipose tissue as compared with WT controls. In addition, phosphorylation of insulin receptor substrate-1 and Akt2 in response to insulin treatment in isolated FAIM-KO hepatocytes was also markedly attenuated. Altogether, our data indicate that FAIM is a novel regulator of insulin signalling and plays an essential role in energy homoeostasis. These findings may shed light on the pathogenesis of obesity and hepatosteatosis.

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“…NKT cells contribute to autoimmune diseases either through defective immunoregulation or inappropriate activation . A recent study has also shown that autoimmune B cells, via altered presentation of self‐lipids by CD1d, cause overt activation of NKT cells, leading to NKT cell death . Because NKT cell/B‐cell interactions are important in driving normal humoral responses as well as autoimmunity, it would be interesting to study the role of the JAK/STAT pathway in regulating CD1d‐mediated antigen presentation under those conditions.…”

Section: Discussionmentioning

confidence: 99%

STAT3 promotes CD1d‐mediated lipid antigen presentation by regulating a critical gene in glycosphingolipid biosynthesis

et al. 2015

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SummaryCytokines that regulate the immune response signal through the Janus kinase / signal transducer and activation of transcription (JAK/STAT) pathway, but whether this pathway can regulate CD1d-mediated lipid antigen presentation to natural killer T (NKT) cells is unknown. Here, we found that STAT3 promotes antigen presentation by CD1d. Antigen-presenting cells (APCs) in which STAT3 expression was inhibited exhibited markedly reduced endogenous lipid antigen presentation to NKT cells without an impact on exogenous lipid antigen presentation by CD1d. Consistent with this observation, in APCs where STAT3 was knocked down, dramatically decreased levels of UDP glucose ceramide glucosyltransferase (UGCG), an enzyme involved in the first step of glycosphingolipid biosynthesis, were observed. Impaired lipid antigen presentation was reversed by ectopic expression of UGCG in STAT3-silenced CD1d + APCs. Hence, by controlling a fundamental step in CD1d-mediated lipid antigen presentation, STAT3 signalling promotes innate immune responses driven by CD1d.

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Aberrant Presentation of Self-Lipids by Autoimmune B Cells Depletes Peripheral iNKT Cells

Cited by 17 publications

References 36 publications

CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells

CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells

Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis

STAT3 promotes CD1d‐mediated lipid antigen presentation by regulating a critical gene in glycosphingolipid biosynthesis

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