Differential immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO) on primary human CD4+ and CD8+ T cells
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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.
KeywordsIndoleamine 2,3-dioxygenase (IDO) GCN2 kinase pathway Kynurenine
CCAAT/enhancer-binding protein homologous protein
The Canadian Institutes of Health Research and British Columbia Professional Fire Fighters’ Burn Fund supported this study. Farshad Forouzandeh and Reza B. Jalili are holding University Graduate Fellowships from the University of British Columbia. Marc Germain is the recipient of a Postdoctoral Fellowship from the Michael Smith Foundation for Health Research. The authors are grateful to Dr. JM Carlin (Department of Microbiology, Miami University, Oxford, OH) for his gift of IDO cDNA.
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