title: Increased CD45RA+ FoxP3(low) regulatory T cells with impaired suppressive function in patients with systemic lupus erythematosus.
abstract: BACKGROUND
  The role of naturally occurring regulatory T cells (Treg) in the control of the development of systemic lupus erythematosus (SLE) has not been well defined. Therefore, we dissect the phenotypically heterogeneous CD4(+)FoxP3(+) T cells into subpopulations during the dynamic SLE development.  METHODLOGY/PRINCIPAL FINDINGS: To evaluate the proliferative and suppressive capacities of different CD4(+) T cell subgroups between active SLE patients and healthy donors, we employed CD45RA and CD25 as surface markers and carboxyfluorescein diacetatesuccinimidyl ester (CFSE) dilution assay. In addition, multiplex cytokines expression in active SLE patients was assessed using Luminex assay. Here, we showed a significant increase in the frequency of CD45RA(+)FoxP3(low) naive Treg cells (nTreg cells) and CD45RA(-)FoxP3(low) (non-Treg) cells in patients with active SLE. In active SLE patients, the increased proportions of CD45RA(+)FoxP3(low) nTreg cells were positively correlated with the disease based on SLE disease activity index (SLEDAI) and the status of serum anti-dsDNA antibodies. We found that the surface marker combination of CD25(+)CD45RA(+) can be used to defined CD45RA(+)FoxP3(low) nTreg cells for functional assays, wherein nTreg cells from active SLE patients demonstrated defective suppression function. A significant correlation was observed between inflammatory cytokines, such as IL-6, IL-12 and TNFα, and the frequency of nTreg cells. Furthermore, the CD45RA(+)FoxP3(low) nTreg cell subset increased when cultured with SLE serum compared to healthy donor serum, suggesting that the elevated inflammatory cytokines of SLE serum may promote nTreg cell proliferation/expansion.
  
  
  CONCLUSIONS
  Our results indicate that impaired numbers of functional CD45RA(+)FoxP3(low) naive Treg cell and CD45RA(-)FoxP3(low) non-suppressive T cell subsets in inflammatory conditions may contribute to SLE development. Therefore, analysis of subsets of FoxP3(+) T cells, using a combination of FoxP3, CD25 and CD45RA, rather than whole FoxP3(+) T cells, will help us to better understand the pathogenesis of SLE and may lead to the development of new therapeutic strategies.
authors.affiliation: Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Pan
authors.forename: Xiangliang
authors.initials: X
authors.lastname: Yuan
authors.forename: Yingxia
authors.initials: Y
authors.lastname: Zheng
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.forename: Jianping
authors.initials: J
authors.lastname: Shan
authors.forename: Fujun
authors.initials: F
authors.lastname: Lin
authors.forename: Gengru
authors.initials: G
authors.lastname: Jiang
authors.forename: Yuan H
authors.initials: YH
authors.lastname: Yang
authors.forename: Die
authors.initials: D
authors.lastname: Wang
authors.forename: Dakang
authors.initials: D
authors.lastname: Xu
authors.forename: Lisong
authors.initials: L
authors.lastname: Shen
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D005452:Fluoresceins / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D013388:Succinimides / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; C418974:FOXP3 protein, human; D005452:Fluoresceins; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D013388:Succinimides; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D017493:Leukocyte Common Antigens