Forouzandeh Farshad, Jalili Reza B, Germain Marc, Duronio Vincent, Ghahary Aziz
BC Professional Fire Fighters' Burn and Wound Healing Research Lab., Department of Surgery, University of British Columbia, 2660 Oak Street, 351-Jack Bell Research Centre, Vancouver, BC, Canada V6H 3Z6.
Mol Cell Biochem. 2008 Feb;309(1-2):1-7. doi: 10.1007/s11010-007-9635-y. Epub 2007 Nov 16.
We have previously demonstrated that indoleamine 2,3-dioxygenase (IDO) expression by skin cells generates a tryptophan deficient environment in which THP-1, Jurkat cells as well as human PBMC are unable to survive. However, the subsets of primary human T cells that are sensitive to tryptophan depletion have not been identified. In this study, we asked whether the proliferation and viability of bystander CD4+ and CD8+ T cells are modulated in response to IDO induced tryptophan deficient environment and if so, whether their response is different. To address these questions, we co-cultured IDO-expressing fibroblasts with bystander human CD4+ and CD8+ T cells for 4 days and then the survival and proliferation rates as well as downstream metabolic pathway of tryptophan degradation in these cells were evaluated. The results showed a marked immunosuppressive effect of IDO expression on both subsets of primary human T cells. Interestingly, there was also a significant difference in the suppressive effect of IDO on proliferation of CD8+ compared to that of CD4+ T cells. The results of subsequent experiments showed that this discrepancy is due to differences in GCN2 kinase pathway activation between these two sets of immune cells. In conclusion, the finding of this study revealed that the proliferation of CD8+ and CD4+ T cells are suppressed in response to tryptophan deficient environment caused by IDO expression and it is more so for CD8+ T than CD4+ T cells.
我们之前已经证明，皮肤细胞表达吲哚胺2,3-双加氧酶（IDO）会产生色氨酸缺乏的环境，在这种环境中，THP-1细胞、Jurkat细胞以及人类外周血单个核细胞（PBMC）均无法存活。然而，对色氨酸耗竭敏感的原代人T细胞亚群尚未得到鉴定。在本研究中，我们探讨了旁观者CD4⁺和CD8⁺T细胞的增殖和活力是否会因IDO诱导的色氨酸缺乏环境而受到调节，如果是，它们的反应是否存在差异。为了解决这些问题，我们将表达IDO的成纤维细胞与旁观者人CD4⁺和CD8⁺T细胞共培养4天，然后评估这些细胞的存活率、增殖率以及色氨酸降解的下游代谢途径。结果显示，IDO表达对原代人T细胞的两个亚群均有显著的免疫抑制作用。有趣的是，与CD4⁺T细胞相比，IDO对CD8⁺T细胞增殖的抑制作用也存在显著差异。后续实验结果表明，这种差异是由于这两组免疫细胞之间GCN2激酶途径激活的差异所致。总之，本研究结果表明，IDO表达导致的色氨酸缺乏环境会抑制CD8⁺和CD4⁺T细胞的增殖，且对CD8⁺T细胞的抑制作用比对CD4⁺T细胞更强。
