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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Alloreactive CD8 T cells rescued from apoptosis during co-stimulation blockade by Toll-like receptor stimulation remain susceptible to Fas-induced cell death
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Alloreactive CD8 T cells rescued from apoptosis during co-stimulation blockade by Toll-like receptor stimulation remain susceptible to Fas-induced cell death

机译：通过Toll样受体刺激共刺激阻断过程中从凋亡中拯救出来的同种反应性CD8 T细胞仍然容易受到Fas诱导的细胞死亡的影响

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Summary: Blockade of co-stimulatory signals to T cells is extremely effective for the induction of transplantation tolerance in immunologically naive rodents. However, infections and inflammation compromise the efficacy of co-stimulation blockade regimens for the induction of tolerance, thereby stimulating the rejection of allografts. Previous studies have shown that stimulation of innate immunity abrogates tolerance induction by preventing the deletion of alloreactive CD8+ T cells that normally occurs during co-stimulation blockade. Although inflammation prevents the deletion of alloreactive T cells during co-stimulation blockade, it is not known if this resistance to cell death is the result of a mechanism intrinsic to the T cell. Here, we used syngeneic bone marrow chimeric mice that contain a trace population of T-cell receptor transgenic alloreactive CD8+ T cells to investigate the early apoptotic signature and activation status of alloreactive T cells following exposure to inflammatory signals during co-stimulation blockade with an antibody specific for CD154. Our findings revealed that the presence of bacterial lipopolysaccharide during co-stimulation blockade enhanced the early activation of alloreactive CD8+ T cells, as indicated by the up-regulation of CD25 and CD69, suppressed Fas ligand expression, and prevented apoptotic cell death. However, alloreactive CD8+ T cells from lipopolysaccharide-treated mice remained sensitive to Fas-mediated apoptosis in vitro. These findings suggest that alloreactive T cells rescued from deletion during co-stimulation blockade by inflammation are still sensitive to pro-apoptotic signals and that stimulating these apoptotic pathways during co-stimulation blockade may augment the induction of tolerance.
机译：摘要：对T细胞的共刺激信号的阻断对免疫学上幼稚的啮齿类动物的移植耐受诱导极为有效。然而，感染和炎症损害了共刺激阻断方案诱导耐受性的功效，从而刺激了同种异体移植的排斥。先前的研究表明，先天免疫的刺激通过防止通常在共刺激阻滞过程中发生的同种反应性CD8 + T细胞的缺失而消除了耐受性诱导。尽管炎症阻止了共刺激阻断过程中同种异体T细胞的缺失，但尚不清楚这种对细胞死亡的抗性是否是T细胞固有机制的结果。在这里，我们使用了含有痕量T细胞受体转基因同种反应性CD8 + T细胞的同基因骨髓嵌合小鼠，研究了在与抗体共同刺激阻断过程中暴露于炎症信号后同种反应性T细胞的早期凋亡特征和激活状态CD154专用。我们的发现表明，共刺激阻断过程中细菌脂多糖的存在增强了同种反应性CD8 + T细胞的早期活化，这可以通过CD25和CD69的上调来表达，抑制Fas配体的表达，并防止凋亡细胞的死亡。但是，来自脂多糖处理的小鼠的同种反应性CD8 + T细胞在体外仍然对Fas介导的细胞凋亡敏感。这些发现表明，在通过炎症共刺激阻断过程中从缺失中拯救出来的同种异体反应性T细胞仍然对促凋亡信号敏感，并且在共刺激阻断过程中刺激这些凋亡途径可能会增强耐受性。

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