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

Abstract

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-γ), 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-γ 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-γ-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.

Analysis of the dysregulation between regulatory B and T cells (Breg and Treg) in human immunodeficiency virus (HIV)-infected patients

“…We demonstrated that CD19 + TIM-1 + could also participate in the IL-10 production in HIV + individuals, which has already been described in mice, where TIM-1 defects in B cells reduce the production of Breg IL-10 [40]. Moreover, it was demonstrated that IL-10-secreting B cells were concentrated in the TIM-1 + CD19 + B cells in healthy [41] and in HIV + individuals [19]. This IL-10 production by TIM-1 + B cells is related to their ability to inhibit IFN-γ production and to upregulate Foxp3 expression in T cells [41].…”

“…Moreover, it was demonstrated that IL-10-secreting B cells were concentrated in the TIM-1 + CD19 + B cells in healthy [41] and in HIV + individuals [19]. This IL-10 production by TIM-1 + B cells is related to their ability to inhibit IFN-γ production and to upregulate Foxp3 expression in T cells [41]. TIM-1 + B cells were also determined to promote Foxp3 expression in CD4+ T cells in acute respiratory distress syndrome [42].…”

CD19+CD24hiCD38hi B Cell Dysfunction in Primary Biliary Cholangitis

“…Tim-1 defects also increase proinflammatory cytokine production, including IL-1, IL-6, and TNF-α [20]. Further, Tim-1-deficient B cells enhance Th1 and Th17 cell responses and inhibit regulatory T cells [20,22].…”

Altered frequency of CD24highCD38high transitional B cells in patients with cardiac involvement of chronic Chagas disease

“…Several subsets of IL-10 producing B cells have been described in humans, their definition depending on the disease under study, the immunological context and the stimulation conditions. These include CD1d + CD5 + (43,44), Tim-1 + (15,16), immature transitional CD24 hi CD38 hi (11,41) and memory CD24 high CD27 + B cells (12).…”

“…However, and due to the absence of subset-specific membrane markers or transcription factors, IL-10 secretion is still the hallmark feature used to distinguish Breg from the rest of the B cells (9,10). In humans, different B cell lineages that secrete this cytokine and have regulatory functions have been described, such as CD19 + CD24 high CD38 high (11), CD19 + CD24 high CD27 + (12), CD19 + CD5 + CD1d + (13,14), CD19 + Tim-1 + (15,16) and CD19 + CD25 + CD71 + CD73cells (7), depending on the stimulation conditions and the markers used to identify them. Nowadays, the majority of the studies in human samples pinpoint the CD19 + CD24 high CD38 high immature transitional B cell population as the most representative phenotypic signature of Breg cells (17).…”