Suppressive effects of ethanol exposure on the ability of DCs to present endogenous peptides to allogeneic T cells have been demonstrated by several in vitro and in vivo investigations (5, 8, 20, 21, 30).

Moreover, the inhibitory effects of ethanol on DC presentation of exogenous antigens were recently explored (15, 21).

In this regard, Mandrekar et al. found that in vitro exposure of monocyte-derived human myeloid DCs to ethanol inhibited presentation of tetanus toxoid antigen to memory T cells (21).

※tetanus toxoid: 培養した破傷風菌から得られた毒素をホルマリンで不活化したもの

Heinz and Waltenbaugh revealed that OVA presentation by CD8+ splenic DCs to transgenic primary DO11.10 CD4+ T cells was impaired.

Furthermore, these cocultures were characterized by reduced secretion of IL-2, IL-12p70, IFN-γ, IL-17, and IL-6 (15).

In addition, the generation of HCV NS5-specific CTL activity via genetic immunizations was also impaired in a chronic ethanol-fed murine model.

Collectively, these studies suggest that priming of both CD4+ and CD8+ T cells by DCs is diminished as a consequence of chronic ethanol exposure (1).

※priming: 初回抗原刺激。ペプチドを結合(ロード)させたMHC分子をナイーブT細胞に抗原提示する際、補助刺激分子とサイトカインを同時に提示することで分化と増殖を誘導する

It appears, however, that the antigen-specific CD4+ and CD8+ T cells themselves are not abnormal; rather, it is the action of ethanol on DCs that produces such T-cell defects as those shown here and in a previous investigation (1).

Despite accumulating evidence revealing impaired allogeneic and autologous antigen presentation by DCs derived from chronically ethanol-fed mice compared to that of DCs obtained from animals on an isocaloric control diet, the underlying cellular mechanisms responsible for reduced antigen presentation are poorly understood.

※autologous: 自己由来の、自系の。autologous mixed lymphocyte reaction 「自己混合リンパ球反応」

Previously, it was suggested that chronic ethanol exposure does not impair antigen uptake pathways by DCs (1).

Therefore, in this investigation, the fate of exogenous OVA protein following uptake by DCs was examined, with the aim of determining the possible effects of ethanol on antigen processing, as measured by degradation, to the final destination of peptide arrival on the cell surface in the context of MHCII presentation as well as cross-presentation by MHCI.

Through phagocytosis or pinocytosis, dendritic cells capture exogenous antigens and process them in the lysosome after they enter the endocytic pathway (18).

In such a process, ethanol has the potential to disrupt the uptake and degradation of the antigen into its peptides, which would in turn affect the loading of the peptide on the MHCI/II complex.

Our findings, however, reveal that the degradation of complex antigens is not affected by high ethanol intake, because the kinetics of the endocytosed full-length OVA protein or GFP were comparable in DCs derived from ethanol- and isocaloric control diet-fed mice (Fig. 2).
なぜなら、エンドサイトーシスされた完全長の卵白アルブミンや緑色蛍光タンパク質の動態は、エタノール食マウス由来のDCと同カロリーコントロール食マウス由来のDCで似たような結果が出たからである(Fig. 2)。

Furthermore, processing of the full-length intact protein in order to form the peptide-MHCII complex is necessary to trigger T-cell activation.

If antigen processing was indeed altered by ethanol, then presenting DCs with a short, ready-to-present peptide could restore T-cell activation in affected ethanol-derived DCs.

However, when the DCs were pulsed with low concentrations of the highly immunogenic OVA323-339 peptide--the 17-amino-acid epitope to which DO11 T cells are reactive--the DO11 T-cell line and both CD4+ T-cell and pan-T-cell activation by DCs prepared from ethanol-fed mice were still impaired, as seen by their lower IL-2 levels than those with DCs isolated from control mice (Fig. 3A to C).
しかし、高い免疫原性を持つ卵白アルブミン323-339残基ペプチド (DO11のT細胞が反応する17アミノ酸エピトープ)を低濃度でエタノール食マウス由来のDCに適用しても、DO11のT細胞系列 (CD4陽性T細胞と汎T細胞)は活性化できないままだった。
コントロール食マウスから分離したDCよりも、IL-2濃度は低かったことが観察された(Fig.3 AからC)。

These observations collectively reveal that ethanol not only inhibits alloreactivity exhibited by T cells cocultured with DCs but also affects the presentation of exogenous small peptides by DCs to subsequently activate CD4+ T cells, and this presentation defect does not rely on an antigen degradation pathway.

※alloreactivity: 同種反応性。同一の動物種であるが遺伝的に異なる系統(同種異系)の個体に対する反応。アロ反応性

Previously, MHC class II but not class I antigens were reported to be expressed differentially on DC surfaces derived from 8-week chronically ethanol-fed and isocaloric control diet-fed mice under these experimental conditions (1).

In line with this observation, our results demonstrated that the individual peptide 48-61-MHCII complexes were strikingly lower in dendritic cells obtained from ethanol-fed mice than in those isolated from control mice after they were each pulsed with HEL protein (Fig. 4A).
エタノール食を与えたマウスから得られた樹状細胞とコントロール食のマウスから分離した樹状細胞にそれぞれHELタンパク質を適用すると、ペプチド48-61残基とMHCクラスIIの複合体は、エタノール食マウス由来の樹状細胞で著しく低いことが明らかになった(Fig. 4A)。

This finding suggests that the observed low abundance of MHCII molecules on the DC surface, as well as impaired peptide loading or interrupted transport of the peptide-MHCII complex to the DC surface, may together or separately be responsible for reduced peptide-MHCII complex presentation.

by travelair4000ext | 2013-02-06 10:27 | 翻訳  

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