title: Mesenchymal stromal cells augment CD4+ and CD8+ T-cell proliferation through a CCL2 pathway.
abstract: OBJECTIVE
  Mesenchymal stromal cells (MSC) derived from bone marrow are immunosuppressive in vitro and in vivo. Recent evidence, however, has shown that in certain settings, MSC can also be immunostimulatory. The mechanisms involved in this process are largely unknown.
  
  
  METHODS
  Mouse spleen T cells were stimulated with allogeneic mixed lymphocyte reaction (MLR) or anti-CD3/CD28 beads and treated with autologous bone marrow MSC or MSC-conditioned medium. CD4+ and CD8+ T-cell proliferation was analyzed after treatment.
  
  
  RESULTS
  We show that MSC have both suppressive and stimulatory functions toward T cells after stimulation with anti-CD3/CD28 beads or in an MLR. This depended on the ratio of MSC to responder T cells, with low numbers of MSC increasing and higher numbers inhibiting T-cell proliferation. Immunostimulatory function was mediated, in part, by soluble factors. MSC immunosuppression of the MLR was indirect and related to inhibition of antigen-presenting cell maturation. Direct effects of MSC-conditioned medium during anti-CD3/CD28 stimulated proliferation were entirely stimulatory and required the presence of the T-cell receptor. MSC supernatant contained both CCL2 and CCL5 at high levels, but only CCL2 level correlated with the ability to augment proliferation. An anti-CCL2 antibody blocked this proliferative activity.
  
  
  CONCLUSIONS
  CCL2 plays an important role in the immunostimulatory function of MSC, and we further hypothesize that the immunomodulatory role of MSC is determined by a balance between inhibitory and stimulatory factors, suggesting the need for caution when these cells are investigated in clinical protocols.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Division of Thoracic Surgery, University Health Network, Toronto, Ontario, Canada.
authors.forename: Yingzhe
authors.initials: Y
authors.lastname: Zhou
authors.forename: Andrea
authors.initials: A
authors.lastname: Day
authors.forename: Siba
authors.initials: S
authors.lastname: Haykal
authors.forename: Armand
authors.initials: A
authors.lastname: Keating
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002450:Cell Communication; D048708:Cell Growth Processes / Q000187:drug effects; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006801:Humans; D056747:Immunomodulation; D007959:Lymphocyte Culture Test, Mixed; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
chemical_list: D017077:Culture Media, Conditioned
keywords: MSC; T cells; allogeneic MLR; immunostimulation; immunosuppression