Decreased frequencies and impaired functions of the CD31⁺ subpopulation in T_reg cells associated with decreased FoxP3 expression and enhanced T_reg 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)-β1 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.