title: Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators.
abstract: Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that is implicated in suppressing T-cell immunity in normal and pathologic settings. Here, we describe that spontaneous cytotoxic T-cell reactivity against IDO exists not only in patients with cancer but also in healthy persons. We show that the presence of such IDO-specific CD8(+) T cells boosted T-cell immunity against viral or tumor-associated antigens by eliminating IDO(+) suppressive cells. This had profound effects on the balance between interleukin-17 (IL-17)-producing CD4(+) T cells and regulatory T cells. Furthermore, this caused an increase in the production of the proinflammatory cytokines IL-6 and tumor necrosis factor-α while decreasing the IL-10 production. Finally, the addition of IDO-inducing agents (ie, the TLR9 ligand cytosine-phosphate-guanosine, soluble cytotoxic T lymphocyte-associated antigen 4, or interferon γ) induced IDO-specific T cells among peripheral blood mononuclear cells from patients with cancer as well as healthy donors. In the clinical setting, IDO may serve as an important and widely applicable target for immunotherapeutic strategies in which IDO plays a significant regulatory role. We describe for the first time effector T cells with a general regulatory function that may play a vital role for the mounting or maintaining of an effective adaptive immune response. We suggest terming such effector T cells "supporter T cells."
authors.affiliation: Center for Cancer Immune Therapy (CCIT), Department of Hematology, Copenhagen University Hospital, Herlev, Denmark.
authors.forename: Rikke Baek
authors.initials: RB
authors.lastname: Sørensen
authors.forename: Sine Reker
authors.initials: SR
authors.lastname: Hadrup
authors.forename: Inge Marie
authors.initials: IM
authors.lastname: Svane
authors.forename: Mads Christian
authors.initials: MC
authors.lastname: Hjortsø
authors.forename: Per
authors.initials: P
authors.lastname: Thor Straten
authors.forename: Mads Hald
authors.initials: MH
authors.lastname: Andersen
mesh_terms: D056704:Adaptive Immunity; D000956:Antigens, Viral; D001483:Base Sequence; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D058965:MART-1 Antigen / Q000276:immunology; D008297:Male; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000145:classification / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D017931:DNA Primers; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D020381:Interleukin-17; D058965:MART-1 Antigen; C548667:MLANA protein, human; D034741:RNA, Small Interfering