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ABSTRACTTransposable elements (TEs) have been seen as selfish genetic elements that can propagate in a host genome. Their propagation success is however hindered by a combination of mechanisms such as mutations, selection, and their epigenetic silencing by the host genome. As a result, most copies of TEs in a given genome are dead relics: their sequence is too degenerated to allow any transposition. Nevertheless, these TE relics often, but not always, remain epigenetically silenced, and if not to prevent transposition anymore, one can wonder the reason for this phenomenon. The mere self-perpetuating loop inherent to epigenetic silencing could alone explain that even when inactive, TE copies remain silenced. Beyond this process, nevertheless, antagonistic selective forces are likely to act on TE relic silencing. Especially, without the benefit of preventing transposition, TE relic silencing may prove deleterious to the host fitness, suggesting that the maintenance of TE relic silencing is the result of a fine, and perhaps case-by-case, evolutionary trade-off between beneficial and deleterious effects. Ultimately, the release of TE relics silencing may provide a ‘safe’ ground for adaptive epimutations to arise. In this review, we provide an overview of these questions in both plants and animals.

CD8 lymphocytes play a role in aortic valve inflammation leading to aortic valve calcification (AVC). RANK is a transmembrane protein that is important in osteoclast differentiation and calcification. β-glucosylceramide (β-GC) together with β-lactosylceramide (β-LC), the 1:1 combination of β-glucosylceramide and β-lactosylceramide, designated “IGL,” exerts an immune modulatory effect in various inflammatory disorders in a CD8- and NKT (natural killer T cell)-dependent manner. We hypothesized that IGL may affect the inflammatory condition associated with AVC. AVC was induced in rats by oral administration of a high-adenine, high-phosphorus diet and was assessed by multislice computer tomography. Administration of this diet was associated with a marked increase in CD8 and NKT lymphocyte accumulation in the aortic valve. Administration of IGL led to marked suppression of RANK expression, associated with inhibition of both NKT and CD8 lymphocyte accumulation in the aortic valve. These effects were associated with a significant improvement in the degree of AVC in IGL-treated animals (25 and 53 by Agatston Score, in IGL-treated and controls, respectively). CD8 and NKT lymphocytes play a role in the pathogenesis of AVC, and RANK-mediated NKT inhibition by β-glycosphingolipids can alleviate AVC.

β-glucosylceramide has been shown to affect natural killer T cell function in models of inflammation. We, therefore, investigated the effects of different β- glycosphingolipids, including β-glucosylceramide, on STAT (signal transducers and activators of transcription) signaling pathways and determined whether these effects were mediated by lipid raft microdomains and/or CD1d molecules. The effects of α- and β-structured ligands on the lipid raft protein flotillin-2 were studied in both natural killer T hybridoma cells and leptin-deficient mice. To determine whether CD1d was involved in the effects of the β-glycosphingolipids, an anti-CD1d blocking antibody was used in a cell proliferation assay system. The downstream effects on the protein phosphorylation levels of STAT1, STAT3, and STAT6 were examined in both immune-mediated hepatitis and hepatoma models. The effects of β-glycosphingolipids on the STAT signaling pathways were found to be dependent on CD1d. Lipid rafts were affected by both the dose and ratio of the β-glycosphingolipids and the acyl chain length, and these effects were followed by downstream effects on STAT proteins. Our results show that β-glycosphingolipids have beneficial effects in natural killer T cell-dependent immune-mediated metabolic and malignant animal models in vivo.

The aim of this study was to determine the effect of β-glycosphingolipids on intra-hepatic natural killer T (NKT) lymphocyte regulatory function and on lymphocyte trapping via alteration of cell membrane lipid rafts. Immune-mediated colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid. Mice were treated with β-lactosylceramide (LC), β-glucosylceramide (GC), β-galactosylceramide, ceramide, or a combination of both GC and LC (IGL), or solvent alone. Lipid rafts were investigated by fluorescence-activated cell sorting analysis of ganglioside-GM1 and fluorescence microscopy of structure. Administration of β-glycosphingolipids resulted in an increased intrahepatic/peripheral NKT ratio, increased intrahepatic CD8+ lymphocyte trapping, decreased serum interferon-γ (IFN-γ) levels and decreased serum IFN-γ/interleukin-10 ratio. Administration of GC, LC, or IGL significantly altered the levels of GM1, a key marker of lipid rafts, on NKT regulatory lymphocytes. The immune modulatory effect of β-glycosphingolipids was associated with increased survival and significant alleviation of colitis as determined by improvement in both the macroscopic and microscopic scores. In conclusion, administration of β-glycosphingolipids increased NKT regulatory lymphocyte redistribution and intrahepatic CD8+T lymphocyte trapping, resulting in alleviation of immune-mediated colitis. The effects of these naturally occurring compounds were associated with modification of the T lymphocyte lipid raft structure, which is a site for immune modulation.

T lymphocyte‐expressing natural killer (NK) cell markers (NKT cells) play a role in immune regulation. Our aim was to evaluate the in vivo effect of adoptive transfer of immune‐programmed NKT cells. Colitis was induced in C57/B6 mice by 2,4,6‐trinitrobenzenesulfonic acid. NKT, CD4, CD8 lymphocytes, and dendritic cells (DC) were prepared from spleens of naive mice, animals with colitis, and animals with colitis that were orally tolerized. Subsets of splenocytes, NKT, CD4, and CD8 and NKT+CD4, NKT+CD8, and NKT+DC lymphocytes were prepared. Assessment of the T helper cell type 1 (Th1)/Th2 cytokine secretion paradigm in vitro was performed before and following exposure to the antigen. Adoptive transfer of ex vivo immune‐programmed lymphocytes from each group was performed into recipient mice, followed by colitis induction. Ex vivo exposure of NKT cells harvested from mice with colitis‐to‐colitis proteins [colitis‐extracted proteins (CEP)] led to a Th2 cytokine shift. The interleukin (IL)‐4/interferon‐γ (IFN‐γ) ratio increased for NKT harvested from colitis‐harboring mice following exposure to CEP. Adoptive transfer of NKT lymphocytes harvested from colitis‐harboring mice, which were ex vivo‐educated, significantly alleviated experimental colitis in vivo. Intrahepatic NKT lymphocytes increased significantly in mice transplanted with NKT lymphocytes harvested from colitis‐harboring donor mice, which were ex vivo‐exposed to CEP, similar to mice transplanted with NKT lymphocytes harvested from tolerized donors. Exposure of NKT cells to the disease‐target antigen induced a significant increase in the IL‐4/IFN‐γ cytokine ratio. Adoptive transfer of a relatively small number of immune‐programmed NKT cells induced a systemic Th1 to Th2‐immune shift and alleviated immune‐mediated colitis.

It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor growth and the development of lung metastases, but only in advanced tumors. In immune-deficient NOD-SCID mice the effect of splenectomy on tumor growth and metastatic spread disappeared. Splenectomy significantly reduced the presence of MDSC, and especially monocytic-MDSC in the circulation and inside the tumor. Specific reduction of the CCR2+ subset of monocytic MDSC was demonstrated, and the importance of the CCL2-CCR2 axis was further shown by a marked reduction in CCL2 following splenectomy. These changes were followed by changes in the macrophages contents of the tumors to become more antitumorigenic, and by increased activation of CD8+Cytotoxic T-cells (CTL). By MDSC depletion, and adoptive transfer of MDSCs, we demonstrated that the effect of splenectomy on tumor growth was substantially mediated by MDSC cells. We conclude that the spleen is an important contributor to tumor growth and metastases, and that splenectomy can blunt this effect by depletion of MDSC, changing the amount and characteristics of myeloid cells and enhancing activation of CTL.