title: Tryptophan concentration is the main mediator of the capacity of adipose mesenchymal stromal cells to inhibit T-lymphocyte proliferation in vitro.
abstract: OBJECTIVE
  Mesenchymal stromal cells (MSCs) have immunomodulatory properties that are mediated by cell-to-cell interactions and paracrine effects through soluble factors, among which tryptophan (Trp) conversion into kynurenine (Kyn) through the enzymatic activity of indoleamine 2,3-dioxygenase has been proven to be of special relevance. However, the respective role of Trp depletion and/or Kyn accumulation on the inhibition of T-cell proliferation by MSCs remains unclear.
  
  
  METHODS
  The effect of supplementation with increasing concentrations of Trp on the capacity of MSCs to inhibit T-lymphocyte proliferation in vitro was investigated.
  
  
  RESULTS
  We report that Trp supplementation impairs the capacity of adipose mesenchymal stromal cells (ASCs) to inhibit T-cell proliferation, despite the accumulation of very high concentrations of Kyn in the medium (>200 μmol/L). Moreover, Trp supplementation after 72 h of peripheral blood mononuclear cell:ASC co-culture, once the inhibitory effect of ASCs was established, reverted ASC inhibition and restored T-cell proliferation. Addition to stimulated lymphocytes of Kyn inhibited T proliferation in 3 of 10 peripheral blood mononuclear cell donors, but at different concentrations, suggesting that sensitivity of lymphocytes to Kyn might be donor-dependent.
  
  
  CONCLUSIONS
  Our results confirm the relevance of Trp metabolism as a key mediator of the immunomodulatory properties of ASCs and clarify the respective roles of the Trp/Kyn balance.
authors.affiliation: TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Menta
authors.affiliation: TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Mancheño-Corvo
authors.affiliation: TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Del Río
authors.affiliation: TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ramírez
authors.affiliation: TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: DelaRosa
authors.affiliation: TiGenix NV, Leuven, Belgium.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Dalemans
authors.affiliation: TiGenix SAU, Parque Tecnológico de Madrid, Madrid, Spain. Electronic address: eleuterio.lombardo@tigenix.com.
authors.forename: Eleuterio
authors.initials: E
authors.lastname: Lombardo
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014364:Tryptophan / Q000494:pharmacology*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D014364:Tryptophan
keywords: adipose; immunosuppression; mesenchymal stromal cells; tryptophan metabolism