title: Heme oxygenase-1 restores impaired GARPCD4⁺CD25⁺ regulatory T cells from patients with acute coronary syndrome by upregulating LAP and GARP expression on activated T lymphocytes.
abstract: BACKGROUND
  Accumulating evidence shows that the pathological autoreactive immune response is responsible for plaque rupture and the subsequent onset of acute coronary syndrome (ACS). Naturally occurring CD4(+)CD25(+)regulatory T cells (nTregs) are indispensable in suppressing the pathological autoreactive immune response and maintaining immune homeostasis. However, the number and the suppressive function of glycoprotein-A repetitions predominant (GARP) (+) CD4(+) CD25(+) activated nTregs were impaired in patients with ACS. Recent evidence suggests that heme oxygenase-1 (HO-1) can regulate the adaptive immune response by promoting the expression of Foxp3. We therefore hypothesized that HO-1 may enhance the function of GARP(+) CD4(+) CD25(+)Tregs in patients with ACS and thus regulate immune imbalance.
  
  
  METHODS
  T lymphocytes were isolated from healthy volunteers (control, n=30) and patients with stable angina (SA, n=40) or ACS (n=51). Half of these cells were treated with an HO-1 inducer (hemin) for 48 h, and the other half were incubated with complete RPMI-1640 medium. The frequencies of T-helper 1 (Th1), Th2, Th17 and latency-associated peptide (LAP) (+)CD4(+) T cells and the expression of Foxp3 and GARP by CD4(+)CD25(+)T cells were then assessed by measuring flow cytometry after stimulation in vitro. The suppressive function of activated Tregs was measured by thymidine uptake. The levels of transforming growth factor-1 (TGF-β1) in the plasma were measured using enzyme-linked immunosorbent assay (ELISA). The expression levels of the genes encoding these proteins were analyzed by real-time polymerase chain reaction.
  
  
  RESULTS
  Patients with ACS exhibited an impaired number and suppressive function of GARP(+) CD4(+) CD25(+)Tregs and a mixed Th1/Th17-dominant T cell response when compared with the SA and control groups. The expression of LAP in T cells was also lower in patients with ACS compared to patients with SA and the control individuals. Treatment with an HO-1 inducer enhanced the biological activity of GARP(+) CD4(+) CD25(+)Tregs and resulted in increased expression of LAP and GARP by activated T cells.
  
  
  CONCLUSIONS
  The reduced number and impaired suppressive function of GARP(+) CD4(+) CD25(+)Tregs result in excess effector T cell proliferation, leading to plaque instability and the onset of ACS. HO-1 can effectively restore impaired GARP(+) CD4(+) CD25(+)Tregs from patients with ACS by promoting LAP and GARP expression on activated T cells.
authors.affiliation: The Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaoqi
authors.initials: X
authors.lastname: Zhao
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Zhong
authors.forename: Kai
authors.initials: K
authors.lastname: Meng
authors.forename: Kunwu
authors.initials: K
authors.lastname: Yu
authors.forename: Huairui
authors.initials: H
authors.lastname: Shi
authors.forename: Bangwei
authors.initials: B
authors.lastname: Wu
authors.forename: Hasahya
authors.initials: H
authors.lastname: Tony
authors.forename: Jianghao
authors.initials: J
authors.lastname: Zhu
authors.forename: Ruirui
authors.initials: R
authors.lastname: Zhu
authors.forename: Yudong
authors.initials: Y
authors.lastname: Peng
authors.forename: Yi
authors.initials: Y
authors.lastname: Mao
authors.forename: Peng
authors.initials: P
authors.lastname: Cheng
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Mao
authors.forename: Qiutang
authors.initials: Q
authors.lastname: Zeng
mesh_terms: D054058:Acute Coronary Syndrome / Q000276:immunology*; D060050:Angina, Stable / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006427:Hemin; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C087215:LRRC32 protein, human; D008565:Membrane Proteins; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D006427:Hemin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1