title: Suppression of immunodominant antitumor and antiviral CD8+ T cell responses by indoleamine 2,3-dioxygenase.
abstract: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-degrading enzyme known to suppress antitumor CD8(+) T cells (TCD8). The role of IDO in regulation of antiviral TCD8 responses is far less clear. In addition, whether IDO controls both immunodominant and subdominant TCD8 is not fully understood. This is an important question because the dominance status of tumor- and virus-specific TCD8 may determine their significance in protective immunity and in vaccine design. We evaluated the magnitude and breadth of cross-primed TCD8 responses to simian virus 40 (SV40) large T antigen as well as primary and recall TCD8 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 TCD8 responses, indicating that tryptophan metabolites are not responsible for the suppressive effect of IDO in our models. Immunodominant T antigen-specific TCD8 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 TCD8 responses to tumor and viral antigens. Our work also demonstrates that systemic primary and recall TCD8 responses to IAV are controlled by IDO. Inhibition of IDO thus represents an attractive adjuvant strategy in boosting anticancer and antiviral TCD8 targeting highly immunogenic antigens.
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Rytelewski
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Meilleur
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Maryam Atef
authors.initials: MA
authors.lastname: Yekta
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Szabo
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
authors.forename: Nitan
authors.initials: N
authors.lastname: Garg
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University, Hershey, Pennsylvania, United States of America.
authors.forename: Todd D
authors.initials: TD
authors.lastname: Schell
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada ; Department of Medicine, Western University, London, Ontario, Canada ; Department of Pathology, Western University, London, Ontario, Canada ; Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Jevnikar
authors.affiliation: Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada.
authors.forename: Shayan
authors.initials: S
authors.lastname: Sharif
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada ; Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: Bhagirath
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Microbiology and Immunology, Western University, London, Ontario, Canada ; Centre for Human Immunology, Western University, London, Ontario, Canada.
authors.forename: S M Mansour
authors.initials: SM
authors.lastname: Haeryfar
mesh_terms: D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D007108:Immune Tolerance / Q000235:genetics*; D007113:Immunity, Innate; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007737:Kynurenine / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000952:Antigens, Polyomavirus Transforming; D000956:Antigens, Viral; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053645:Interleukin-2 Receptor alpha Subunit; D007737:Kynurenine; D014364:Tryptophan; C525396:1-methyltryptophan