title: Treg Cells Protect Dopaminergic Neurons against MPP+ Neurotoxicity via CD47-SIRPA Interaction.
abstract: OBJECTIVE
  Regulatory T (Treg) cells have been associated with neuroprotection by inhibiting microglial activation in animal models of Parkinson's disease (PD), a progressive neurodegenerative disease characterized by dopaminergic neuronal loss in the nigrostriatal system. Herein, we show that Treg cells directly protect dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity via an interaction between the two transmembrane proteins CD47 and signal regulatory protein α (SIRPA).
  
  
  METHODS
  Primary ventral mesencephalic (VM) cells or VM neurons were pretreated with Treg cells before MPP+ treatment. Transwell co-culture of Treg cells and VM neurons was used to assess the effects of the Treg cytokines transforming growth factor (TGF)-β1 and interleukin (IL)-10 on dopaminergic neurons. Live cell imaging system detected a dynamic contact of Treg cells with VM neurons that were stained with CD47 and SIRPA, respectively. Dopaminergic neuronal loss, which was assessed by the number of tyrosine hydroxylase (TH)-immunoreactive cells, was examined after silencing CD47 in Treg cells or silencing SIRPA in VM neurons.
  
  
  RESULTS
  Treg cells prevented MPP+-induced dopaminergic neuronal loss and glial inflammatory responses. TGF-β1 and IL-10 secreted from Treg cells did not significantly prevent MPP+-induced dopaminergic neuronal loss in transwell co-culture of Treg cells and VM neurons. CD47 and SIRPA were expressed by Treg cells and VM neurons, respectively. CD47-labeled Treg cells dynamically contacted with SIRPA-labeled VM neurons. Silencing CD47 gene in Treg cells impaired the ability of Treg cells to protect dopaminergic neurons against MPP+ toxicity. Similarly, SIRPA knockdown in VM neurons reduced the ability of Treg cell neuroprotection. Rac1/Akt signaling pathway in VM neurons was activated by CD47-SIRPA interaction between Treg cells and the neurons. Inhibiting Rac1/Akt signaling in VM neurons compromised Treg cell neuroprotection.
  
  
  CONCLUSIONS
  Treg cells protect dopaminergic neurons against MPP+ neurotoxicity by a cell-to-cell contact mechanism underlying CD47-SIRPA interaction and Rac1/Akt activation.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Zhan
authors.initials: Z
authors.lastname: Liu
authors.forename: Bei-Bei
authors.initials: BB
authors.lastname: Cao
authors.forename: Yi-Hua
authors.initials: YH
authors.lastname: Qiu
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Peng
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D051928:CD47 Antigen / Q000235:genetics* / Q000276:immunology; D002450:Cell Communication; D016923:Cell Death / Q000187:drug effects; D018920:Coculture Techniques; D015194:Diffusion Chambers, Culture; D059290:Dopaminergic Neurons / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004622:Embryo, Mammalian; D005260:Female; D015870:Gene Expression; D016753:Interleukin-10 / Q000494:pharmacology; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000276:immunology
chemical_list: D051928:CD47 Antigen; C497895:Cd47 protein, mouse; C556062:IL10 protein, mouse; D009479:Neuropeptides; C501922:Sirpa protein, mouse; C484602:Rac1 protein, mouse; D011971:Receptors, Immunologic; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D051057:Proto-Oncogene Proteins c-akt; D020830:rac1 GTP-Binding Protein; D015655:1-Methyl-4-phenylpyridinium
keywords: CD47; Dopaminergic neurons; Parkinson's disease; Regulatory T cells; Signal regulatory protein α