Abstract 417: CXCR4 Distinguishes and Maintains Atheroprotective IgM-producing B-1 cells

B1 cells exert protective effects in atherosclerosis through production of anti-inflammatory IgM antibodies recognizing oxidation-specific epitopes, such as MDA-LDL, present in diseased arteries. However, factors mediating B1 IgM production are currently unclear. We evaluated MDA-LDL binding and chemokine receptor expression on human B1 cells in a cohort of subjects undergoing intravascular ultrasound (IVUS) for coronary artery assessment. Results demonstrate that a subset of human B1 cells (~35%) is able to bind MDA-LDL. Moreover, expression of the chemokine receptor CXCR4 on circulating B1 cells associates with increased plasma levels of anti-MDA-LDL IgM antibodies (p=0.0009), and decreased plaque burden in coronary arteries (p=0.0002). Mice with B cell-specific loss of CXCR4 on the atherogenic ApoE -/- background (CXCR4 BKO ) demonstrate fewer B1a cells (n=6-8,p<0.0001) and IgM antibody-secreting cells (n=6,p<0.01) in the bone marrow, and reduced plasma IgM levels (n=6-8,p<0.05), relative to littermate controls (CXCR4 WT ). Furthermore, retroviral-mediated overexpression of CXCR4 on B1a cells in vivo is associated with increased B1a localization to the bone marrow (p<0.01) and increased circulating levels of anti-MDA-LDL IgM antibodies (p<0.05). To determine the atheroprotective role of CXCR4 on the B1a cell subset, we adoptively transferred CXCR4 WT or CXCR4 BKO B1a cells into lymphocyte-deficient Rag1 -/- ApoE -/- mice. After 16 weeks of Western diet feeding, recipients given CXCR4 BKO B1a cells demonstrate reduced plasma IgM levels (n=7,p<0.001), and fewer donor B1a cells in the bone marrow and spleen (n=7,p<0.05) compared to recipients given CXCR4 WT B1a cells. Intriguingly, B1a transfer reduces plasma cholesterol levels in mice regardless of CXCR4 expression (n=7,p<0.05). However, CXCR4 further strengthens the atheroprotective ability of B1a cells, as recipients given CXCR4 WT B1a cells have reduced aortic lesion area compared to PBS controls (n=7,p<0.01) while recipients given CXCR4 BKO B1a cells did not attain the same level of protection. Overall, these data suggest that CXCR4 is an important regulator of IgM production and B1a-mediated atheroprotection.