Tim-1+ B cells suppress T cell interferon-gamma production and promote Foxp3 expression, but have impaired regulatory function in coronary artery disease

Atherosclerosis and its associated coronary artery disease (CAD) represent another chronic low-grade inflammatory disorder. Regulatory B cells (Bregs) possess essential functions in maintaining peripheral tolerance and inhibiting pathogenic inflammation through IL-10. Here, we investigated one subset of Bregs, Tim-1(+) B cell, and its role in atherosclerosis and CAD patients. In healthy individuals, IL-10-producing B cells were predominantly found in the Tim-1(+) B cells. Upon stimulation of the B cell receptor (BCR) and Toll-like receptor 9 (TLR-9) by anti-BCR antibodies and CpG, respectively, the Tim-1(+) B cells could further upregulate IL-10 expression. In contrast, the Tim-1(+) B cells were present at normal frequency in CAD patients, but showed impaired capacity to upregulate IL-10 with or without BCR+ CpG stimulation. The stimulated Tim-1(+) B cells from healthy individuals also suppressed expression of interferon gamma (IFN-gamma), an atherogenic cytokine in T cells, in an IL-10-dependent fashion, and strongly promoted the expression of Foxp3 in naive CD4(+) CD45RO(-) T cells. In contrast, the Tim-1(+) B cells from CAD patients were unable to suppress IFN-gamma secretion, and only minimally increased the expression of Foxp3 in naive CD4(+) CD45RO(-) T cells. Despite this, the frequency of Tim-1(+) B cells in the atherosclerotic lesions from CAD patients was inversely correlated with the frequency of IFN-gamma-expressing T cells. Together, these results demonstrated that CAD patients presented an inflammatory disorder in regulatory B cells, which could be used as a therapeutic target.