Decreased frequencies and impaired functions of the CD31+ subpopulation in Treg cells associated with decreased FoxP3 expression and enhanced Treg cell defects in patients with coronary heart disease

Coronary heart disease (CHD) is one of the most common types of organ lesions caused by atherosclerosis, in which CD4+ CD25(+) forkhead box protein 3 (FoxP3(+)) regulatory T cells (T-reg) play an atheroprotective role. However, T-reg cell numbers are decreased and their functions are impaired in atherosclerosis; the underlying mechanisms remain unclear. CD31 plays an important part in T cell response and contributes to maintaining T cell tolerance. The immunomodulatory effects of CD31 are also implicated in atherosclerosis. In this study, we found that decreased frequencies of the CD31(+) subpopulation in T-reg cells (CD31(+) Tr cells) correlated positively with decreased FoxP3 expression in CHD patients. Cell culture in vitro demonstrated CD31(+) Tr cells maintaining stable FoxP3 expression after activation and exhibited enhanced proliferation and immunosuppression compared with the CD31(-) subpopulation in T-reg cells (CD31(-) Tr cells). We also confirmed impaired secretion of transforming growth factor (TGF)-beta 1 and interleukin (IL)- 10 in CD31(+) Tr cells of CHD patients. Further analysis revealed reduced phospho-SHP2 (associated with CD31 activation) and phospho- signal transducer and activator of transcription-5 (STAT- 5) (associated with FoxP3 transcription) levels in CD31(+) Tr cells of CHD patients, suggesting that decreased FoxP3 expression in CD31(+) Tr cells might be because of attenuated SHP2 and STAT- 5 activation. These data indicate that decreased frequencies and impaired functions of the CD31(+) Tr subpopulation associated with decreased FoxP3 expression give rise, at least in part, to T-reg cell defects in CHD patients. Our findings emphasize the important role of the CD31(+) Tr subpopulation in maintaining T-reg cell normal function and may provide a novel explanation for impaired immunoregulation of T-reg cells in CHD.