Suppression of Immunodominant Antitumor and Antiviral CD8+ T Cell Responses by Indoleamine 2,3-Dioxygenase

Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme known to suppress antitumor CD8 + T cells (T CD8 ). The role of IDO in regulation of antiviral T CD8 responses is far less clear. In addition, whether IDO controls both immunodominant and subdominant T CD8 is not fully understood. This is an important question because the dominance status of tumor- and virus-specific T CD8 may determine their significance in protective immunity and in vaccine design. We evaluated the magnitude and breadth of cross-primed T CD8 responses to simian virus 40 (SV40) large T antigen as well as primary and recall T CD8 responses to influenza A virus (IAV) in the absence or presence of IDO. IDO −/− mice and wild-type mice treated with 1-methyl-D-tryptophan, a pharmacological inhibitor of IDO, exhibited augmented responses to immunodominant epitopes encoded by T antigen and IAV. IDO-mediated suppression of these responses was independent of CD4 + CD25 + FoxP3 + regulatory T cells, which remained numerically and functionally intact in IDO −/− mice. Treatment with L-kynurenine failed to inhibit T CD8 responses, indicating that tryptophan metabolites are not responsible for the suppressive effect of IDO in our models. Immunodominant T antigen-specific T CD8 from IDO −/− mice showed increased Ki-67 expression, suggesting that they may have acquired a more vigorous proliferative capacity in vivo . In conclusion, IDO suppresses immunodominant T CD8 responses to tumor and viral antigens. Our work also demonstrates that systemic primary and recall T CD8 responses to IAV are controlled by IDO. Inhibition of IDO thus represents an attractive adjuvant strategy in boosting anticancer and antiviral T CD8 targeting highly immunogenic antigens.