title: Umbilical cord mesenchymal stem cells inhibit the differentiation of circulating T follicular helper cells in patients with primary Sjögren's syndrome through the secretion of indoleamine 2,3-dioxygenase.
abstract: OBJECTIVE
  The aim of this study was to investigate the effect of umbilical cord mesenchymal stem cells (UC-MSCs) on circulating T follicular helper (cTfh) cells in primary SS (pSS) patients.
  
  
  METHODS
  The percentage of CXCR5(+)PD-1(+)CD4(+) T cells in peripheral blood mononuclear cells (PBMCs) was analysed by flow cytometry. PBMCs were co-cultured with UC-MSCs by cell-to-cell contact or in a trans-well system. Naive CD4(+) T cells were isolated from PBMCs and then co-cultured with UC-MSCs under Tfh cell-polarizing conditions. The percentage of CXCR5(+)PD-1(+)CD4(+) T cells, carboxyfluorescein succinimidyl ester (CFSE) fluorescence intensity and annexin V were determined by flow cytometric analysis. Real-time PCR and Luminex cytokine assay were performed to detect mRNA expression and supernatant protein levels. The activity of indoleamine 2,3-dioxygenase (IDO) was measured by HPLC.
  
  
  RESULTS
  Increased frequency of cTfh cells was found in pSS patients and was positively correlated with serum anti-La/SSB levels and the European League Against Rheumatism SS Disease Activity Index score. In vitro, UC-MSCs suppressed the differentiation and proliferation of cTfh cells. Real-time PCR analysis showed significantly higher IDO mRNA expression on UC-MSCs when co-cultured with naive CD4(+) T cells under Tfh cell-polarizing conditions in pSS patients. However, IDO mRNA expression on UC-MSCs was only a little higher when UC-MSCs were co-cultured with naive CD4(+) T cells in a trans-well system. In addition, HPLC showed increased IDO enzymic activity in the supernatant of UC-MSCs co-cultured with naive CD4(+) T cells under Tfh cell-polarizing conditions in pSS. The addition of the IDO inhibitor 1-MT partly reversed the suppressive effect of UC-MSCs on the differentiation of cTfh cells.
  
  
  CONCLUSIONS
  These results suggest an inhibitory effect of UC-MSCs on the differentiation of cTfh cells via the secretion of IDO, and soluble factors secreted by activated CD4(+) T cells might contribute to IDO secretion by UC-MSCs.
authors.affiliation: Department of Immunology and Rheumatology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu and Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Immunology and Rheumatology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu and Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, People's Republic of China.
authors.forename: Dinglei
authors.initials: D
authors.lastname: Su
authors.affiliation: Department of Immunology and Rheumatology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu and Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Immunology and Rheumatology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu and Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, People's Republic of China.
authors.forename: Xuebing
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Immunology and Rheumatology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu and Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Immunology and Rheumatology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu and Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, People's Republic of China. lingyunsun2012@163.com.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000974:Antibodies, Antinuclear / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000201:enzymology* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology*; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D000974:Antibodies, Antinuclear; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; C035356:SS-A antibodies; C035357:SS-B antibodies
keywords: 3-dioxygenase; Sjögren’s syndrome; T follicular helper cell; indoleamine 2; mesenchymal stem cell