Defective circulating CD4+LAP+ regulatory T cells in patients with dilated cardiomyopathy.
There has been increasing evidence that chronic immune activation plays critical roles in the pathogenesis of DCM. CD4(+) LAP(+) Tregs are a newly identified T cell subset with suppressive function on the immune response. This study was designed to investigate whether the circulating frequency and function of CD4(+)LAP(+) Tregs would be impaired in patients with DCM. The results demonstrated that DCM patients had a significantly lower frequency of circulating CD4(+)LAP(+) Tregs compared with control donors. CD4(+)LAP(+) Tregs from DCM patients showed compromised function to suppress proliferation of CD4(+) LAP(-)CD25(int/low) T cells and proliferation and IgG production of B cells. Moreover, B cell proliferation and IgG subset production could be directly suppressed by CD4(+) LAP(+) Tregs. TGF-β and contact-dependent mechanisms were involved in CD4(+)LAP(+) Treg-mediated suppression. Correlation analysis suggested that CD4(+)LAP(+) Treg frequency was positively correlated with LVEF and negatively correlated with serum IgG3 and NT-proBNP concentration in patients with DCM. Our results are the first to demonstrate that the frequencies of CD4(+)LAP(+) Tregs in patients with DCM are reduced and that their suppressive function is compromised. Defective CD4(+) LAP(+) Tregs may be an underlying mechanism of immune activation in DCM patients.
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Zheng-Feng
ZF
Zhu
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Ting-Ting
TT
Tang
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Wen-Yong
WY
Dong
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Yuan-Yuan
YY
Li
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Ni
N
Xia
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Wen-Cai
WC
Zhang
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Su-Feng
SF
Zhou
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Jing
J
Yuan
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Meng-Yang
MY
Liao
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Jing-Jing
JJ
Li
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Jiao
J
Jiao
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Shao-Fang
SF
Nie
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Qing
Q
Wang
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Xin
X
Tu
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Cheng-Qi
CQ
Xu
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Yu-Hua
YH
Liao
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Guo-Ping
GP
Shi
*Laboratory of Cardiovascular Immunology, Institute of Cardiology, Union Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China; Key Laboratory of Biological Targeted Therapy of the Ministry of Education, Wuhan, China; Key Laboratory of Molecular Biophysics of the Ministry of Education, Cardio-X Institute, College of Life Science and Technology and Center of Human Genome Research, Huazhong University of Science and Technology, Wuhan, China; and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Xiang
X
Cheng
D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology; D018791:CD4 Lymphocyte Count; D002311:Cardiomyopathy, Dilated / Q000097:blood / Q000000981:diagnostic imaging / Q000276:immunology* / Q000503:physiopathology; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000097:blood; D008213:Lymphocyte Activation / Q000276:immunology; D008211:Lymphocyte Cooperation / Q000276:immunology; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D013318:Stroke Volume; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000473:pathology*; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000097:blood*; D014463:Ultrasonography
D007074:Immunoglobulin G; D010446:Peptide Fragments; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain
B cells; IgG; latency-associated peptide