title: Natural CD4+ T-cell responses against indoleamine 2,3-dioxygenase.
abstract: BACKGROUND
  The enzyme indoleamine 2,3-dioxygenase (IDO) contributes to immune tolerance in a variety of settings. In cancer IDO is expressed within the tumor itself as well as in antigen-presenting cells in tumor-draining lymph nodes, where it endorses the establishment of peripheral immune tolerance to tumor antigens. Recently, we described cytotoxic CD8(+) T-cell reactivity towards IDO-derived peptides.
  
  
  RESULTS
  In the present study, we show that CD4(+) helper T cells additionally spontaneously recognize IDO. Hence, we scrutinized the vicinity of the previously described HLA-A*0201-restricted IDO-epitope for CD4(+) T-cell epitopes. We demonstrated the presence of naturally occurring IDO-specific CD4(+) T cells in cancer patients and to a lesser extent in healthy donors by cytokine release ELISPOT. IDO-reactive CD4(+) T cells released IFN-γ, TNF-α, as well as IL-17. We confirm HLA class II-restriction by the addition of HLA class II specific blocking antibodies. In addition, we detected a trend between class I- and class II-restricted IDO responses and detected an association between IDO-specific CD4(+) T cells and CD8(+) CMV-responses. Finally, we could detect IL-10 releasing IDO-reactive CD4(+) T cells.
  
  
  CONCLUSIONS
  IDO is spontaneously recognized by HLA class II-restricted, CD4(+) T cells in cancer patients and in healthy individuals. IDO-specific T cells may participate in immune-regulatory networks where the activation of pro-inflammatory IDO-specific CD4(+) responses may well overcome or delay the immune suppressive actions of the IDO-protein, which are otherwise a consequence of the early expression of IDO in maturing antigen presenting cells. In contrast, IDO-specific regulatory T cells may enhance IDO-mediated immune suppression.
authors.affiliation: Department of Hematology and Oncology, Center for Cancer Immune Therapy, Copenhagen University Hospital, Herlev, Herlev, Denmark.
authors.forename: Shamaila
authors.initials: S
authors.lastname: Munir
authors.forename: Stine Kiaer
authors.initials: SK
authors.lastname: Larsen
authors.forename: Trine Zeeberg
authors.initials: TZ
authors.lastname: Iversen
authors.forename: Marco
authors.initials: M
authors.lastname: Donia
authors.forename: Tobias Wirenfeldt
authors.initials: TW
authors.lastname: Klausen
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
authors.forename: Per Thor
authors.initials: PT
authors.lastname: Straten
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology; D008875:Middle Aged; D010455:Peptides / Q000378:metabolism / Q000627:therapeutic use; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000939:Epitopes; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D000949:Histocompatibility Antigens Class II; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma