title: Impaired thymic export and apoptosis contribute to regulatory T-cell defects in patients with chronic heart failure.
abstract: OBJECTIVE
  Animal studies suggest that regulatory T (T(reg)) cells play a beneficial role in ventricular remodeling and our previous data have demonstrated defects of T(reg) cells in patients with chronic heart failure (CHF). However, the mechanisms behind T(reg-)cell defects remained unknown. We here sought to elucidate the mechanism of T(reg-)cell defects in CHF patients.
  
  
  RESULTS
  We performed flow cytometry analysis and demonstrated reduced numbers of peripheral blood CD4(+)CD25(+)FOXP3(+)CD45RO(-)CD45RA(+) naïve T(reg) (nT(reg)) cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+)CD45RA(-) memory T(reg) (mT(reg)) cells in CHF patients as compared with non-CHF controls. Moreover, the nT(reg)/mT(reg) ratio (p<0.01), CD4(+)CD25(+)FOXP3(+)CD45RO(-) CD45RA(+)CD31(+) recent thymic emigrant T(reg) cell (RTE-T(reg)) frequency (p<0.01), and T-cell receptor excision circle levels in T(reg) cells (p<0.01) were lower in CHF patients than in non-CHF controls. Combined annexin-V and 7-AAD staining showed that peripheral T(reg) cells from CHF patients exhibited increased spontaneous apoptosis and were more prone to interleukin (IL)-2 deprivation- and CD95 ligand-mediated apoptosis than those from non-CHF individuals. Furthermore, analyses by both flow cytometry and real-time polymerase chain reaction showed that T(reg)-cell frequency in the mediastinal lymph nodes or Foxp3 expression in hearts of CHF patients was no higher than that of the non-CHF controls.
  
  
  CONCLUSIONS
  Our data suggested that the T(reg)-cell defects of CHF patients were likely caused by decreased thymic output of nascent T(reg) cells and increased susceptibility to apoptosis in the periphery.
authors.affiliation: Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Tang
authors.forename: Zheng-Feng
authors.initials: ZF
authors.lastname: Zhu
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Tu
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.forename: Xin-Ling
authors.initials: XL
authors.lastname: Du
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Xia
authors.forename: Nian-Guo
authors.initials: NG
authors.lastname: Dong
authors.forename: Wei
authors.initials: W
authors.lastname: Su
authors.forename: Ni
authors.initials: N
authors.lastname: Xia
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Yan
authors.forename: Xing-Xing
authors.initials: XX
authors.lastname: Yan
authors.forename: Shao-Fang
authors.initials: SF
authors.lastname: Nie
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Su-Feng
authors.initials: SF
authors.lastname: Zhou
authors.forename: Rui
authors.initials: R
authors.lastname: Yao
authors.forename: Jiang-Jiao
authors.initials: JJ
authors.lastname: Xie
authors.forename: Harish
authors.initials: H
authors.lastname: Jevallee
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Meng-Yang
authors.initials: MY
authors.lastname: Liao
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Michael
authors.initials: M
authors.lastname: Fu
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Liao
authors.forename: Xiang
authors.initials: X
authors.lastname: Cheng
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D002908:Chronic Disease; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006333:Heart Failure / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism*
chemical_list: C418974:FOXP3 protein, human; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit