title: Indoleamine 2,3-dioxygenase mediates inhibition of virus-specific CD8(+) T cell proliferation by human mesenchymal stromal cells.
abstract: OBJECTIVE
  Mesenchymal stromal cells (MSCs) exert broad immunomodulatory functions. We recently demonstrated a strong suppressive effect of MSCs on virus-specific CD8(+) T-cell proliferation. Here, we further explored the underlying mechanism.
  
  
  METHODS
  The role of indoleamine 2,3-dioxygenase (IDO) in inhibition of virus-specific CD8(+) T-cell proliferation by human MSCs was investigated using a mixed lymphocyte peptide culture assay, IDO intracellular staining and IDO inhibition through 1-methyl-DL-tryptophan (1-MT). Moreover, the influence of the number of passages and the seeding density of MSCs on their IDO expression and immunosuppressive ability were investigated.
  
  
  RESULTS
  MSCs with low IDO expression exhibited a reduced suppressive effect on both allo-antigen- and cytomegalovirus (CMV)-specific CD8(+) T-cell proliferation. 1-MT could partially abrogate the suppressive effect. MSCs inhibited CMV-specific CD8(+) T-cell proliferation regardless of the number of passages and the seeding density. IDO expression of MSCs was not significantly affected by the number of passages or the seeding density. In addition, the interferon (IFN)-γ level in the culture system was crucial for MSCs to inhibit the proliferation of CMV-specific CD8(+) T cells.
  
  
  CONCLUSIONS
  MSCs inhibit virus-specific CD8(+) T-cell proliferation through IFN-γ-induced IDO activity, resolving current conflicting reports on this issue and indicating the potential need for prophylaxis and surveillance of virus infection in patients treated with MSCs. In addition, our study makes a contribution to the development of MSC potency assay for clinical use.
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany; Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Hueckelhoven
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Wuchter
authors.affiliation: Center for Innovative Research in Medical and Natural Sciences, Medical Faculty of University of Rzeszow, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Tabarkiewicz
authors.affiliation: Department of Transplantation Immunology, Heidelberg University Hospital, Heidelberg, Germany; Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kleist
authors.affiliation: Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Bieback
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Ho
authors.affiliation: Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: Michael.Schmitt@med.uni-heidelberg.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schmitt
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C028129:tryptophan methyl ester; D007371:Interferon-gamma; D014364:Tryptophan; C525396:1-methyltryptophan
keywords: indoleamine 2,3-dioxygenase; interferon-γ; mesenchymal stromal cells; potency assays; virus-specific T cells