Abstract 464: Chemokine Receptor CCR6 Expression on B Cells Augments Local IgM Production and Atheroprotection

Background: CCR6 mediates immune cell recruitment to inflammatory sites and has cell type-specific effects on diet-induced atherosclerosis in mice. Recent studies implicate the local immune responses in the adventitia/perivascular adipose tissue (PVAT) in atherosclerosis development. We have previously demonstrated that adoptive transfer of CD43 - splenocytes (B cells) into B cell deficient μMT -/- ApoE -/- mice results in reduced diet-induced atherosclerosis in a CCR6-dependent manner. Notably, there were significantly greater numbers of B cells in the aorta including PVAT of μMT -/- ApoE -/- mice which received splenic B cells from CCR6 +/+ mice compared to CCR6 -/- mice, despite no difference in B cell numbers in blood, spleen and peritoneal cavity, suggesting that CCR6 expression on B cells is important in B cell aortic homing. Production of IgM antibodies is thought to be a major mechanism whereby B cells limit atherosclerosis development. Yet whether B cells produce IgM locally in the PVAT and whether this is regulated by chemokine receptors such as CCR6 is unknown. Methods and Results: FACS experiments demonstrated high numbers of B cells available in the PVAT than aorta of young ApoE -/- (49121±11190 and 80±11; p<0.001, n=7) mice. ELISPOT experiments demonstrated significantly fewer IgM secreting cells were in the PVAT of ApoE -/- CCR6 -/- mice compared to ApoE -/- CCR6 +/+ mice (100±25 vs 850±150, p<0.05, n=5), despite no differences in IgM secreting cell numbers in spleen and bone marrow. Adoptive transfer of CD43 - splenic B cells from ApoE -/- CCR6 -/- and ApoE -/- CCR6 +/+ mice into secretory IgM deficient ApoE -/- sIgM -/- mice demonstrated significantly reduced atherosclerosis in mice that received B cells from ApoE -/- CCR6 +/+ mice compared to those that received B cells from ApoE -/- CCR6 -/- mice. Moreover, the B cells from ApoE -/- CCR6 +/+ mice attenuated atherosclerosis only when they were capable of secreting IgM. FACS data from human blood demonstrated that circulating B and T cells but not monocytes express CCR6, suggesting potential human relevance to our murine findings. Conclusion: Results provide evidence that CCR6 expression on B cells mediates B cell recruitment into aorta and/or PVAT to provide atheroprotection via IgM secretion.