title: Interferon-γ and tumor necrosis factor-α promote the ability of human placenta-derived mesenchymal stromal cells to express programmed death ligand-2 and induce the differentiation of CD4(+)interleukin-10(+) and CD8(+)interleukin-10(+)Treg subsets.
abstract: OBJECTIVE
  Mesenchymal stromal cells (MSCs) and regulatory T cells (Treg) have been successfully used in treating autoimmune diseases accompanied by abundant inflammatory cytokines such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Therefore, this work investigated the effects of IFN-γ and TNF-α on the ability of human placenta-derived mesenchymal stromal cells (hPMSCs) on inducing the differentiation of CD4(+)interleukin (IL)-10(+)and CD8(+)IL-10(+)Treg subsets.
  
  
  METHODS
  Human PMSCs were co-cultured with T cells in the presence or absence of a trans-well system or anti- programmed death ligand-2 (PDL2) monoclonal antibody (mAb), respectively. CD4(+)IL-10(+)and CD8(+)IL-10(+)Treg subsets, as well as the levels of IL-10 in the supernatants, were detected on this basis. Examinations were conducted to explore the impact of IFN-γ and TNF-α on the expression of PDL2 in hPMSCs. In this process, flow cytometry, Western blot and reverse-transcriptase-polymerase chain reaction were used.
  
  
  RESULTS
  CD4(+)IL-10(+)and CD8(+)IL-10(+)Treg subsets from T cells either non-activated or activated by use of phytohaemagglutinin (PHA) or CD3/CD28mAb significantly increased in the presence of hPMSCs. However, these levels markedly decreased after blocking the expression of PDL2 in hPMSCs. IL-10 followed the same pattern. Furthermore, the percentages of CD4(+)IL-10(+) and CD8(+)IL-10(+)T cells also sharply declined under the trans-well system, whereas the percentages as well as the expression of PDL2 in hPMSCs oppositely raised after hPMSCs pre-stimulated by IFN-γ and TNF-α. IFN-γ could promote the expression of PDL2 partly through the JAK/STAT signaling pathway.
  
  
  CONCLUSIONS
  IFN-γ and TNF-α could promote the ability of hPMSCs in inducing the differentiation of CD4(+)IL-10(+)and CD8(+)IL-10(+)Treg subsets and enhance the expression of PDL2 in hPMSCs. These would benefit the application of hPMSCs in clinical trials.
authors.affiliation: Department of Immunology, Binzhou Medical University, Shandong Province, Yantai, People's Republic of China.
authors.forename: Heng
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Immunology, Binzhou Medical University, Shandong Province, Yantai, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Laboratory, Affiliated Yantai Hospital of Binzhou Medical University, Yantai, People's Republic of China.
authors.forename: Guoyan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, Binzhou Medical University, Shandong Province, Yantai, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Immunology, Binzhou Medical University, Shandong Province, Yantai, People's Republic of China.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Reproductive Medicine, Affiliated Yantai Hospital of Binzhou Medical University, Yantai, People's Republic of China.
authors.forename: Ranran
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Affiliated Yantai Hospital of Binzhou Medical University, Yantai, People's Republic of China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Immunology, Binzhou Medical University, Shandong Province, Yantai, People's Republic of China.
authors.forename: Jiangnan
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Immunology, Binzhou Medical University, Shandong Province, Yantai, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.affiliation: Department of Immunology, Binzhou Medical University, Shandong Province, Yantai, People's Republic of China. Electronic address: xyluan@sohu.com.
authors.forename: Xiying
authors.initials: X
authors.lastname: Luan
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010920:Placenta / Q000166:cytology*; D011247:Pregnancy; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016827:CD8 Antigens; C508609:IL10 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma
keywords: IFN-γ; PDL2; TNF-α; Treg subsets; human placenta; mesenchymal stromal cells