B cell-intrinsic CCR6 expression is required for IgE production in a murine model of galactose-alpha-1,3-galactose syndrome 2267251

Abstract

Abstract Introduction Alpha-gal syndrome (AGS) is acquired through bites from the lone star tick (LST), leading to IgE-mediated reactions to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) present in non-primate mammalian meat and derived products. The mechanisms driving IgE production to alpha-gal are unknown. We previously identified a significant association of CCR6+ memory B cells in the peripheral blood of AGS patients vs healthy controls. Thus, we hypothesized that CCR6 is required for IgE production after tick exposure. Methods Wild-type (WT) and CCR6-/- mice were sensitized with LST extract. After 35 days, serum tick-specific IgE and IgG1 levels were measured by ELISA. To assess the B cell-intrinsic requirement for CCR6, muMT mice were reconstituted with purified B cells from WT or CCR6-/- donors prior to sensitization. Splenocytes were stimulated in vitro with anti-CD40 and IL-4 for 5 days, and expression of eGLT, Bcl6, and Blimp1 were quantified by qPCR. Results CCR6-/- mice showed a significant reduction in tick-specific IgE without affecting IgG1 responses. Reconstitution of muMT mice with WT but not CCR6-/- B cells restored IgE production after tick sensitization, indicating a B cell-intrinsic role for CCR6. In vitro, CCR6-/- splenocytes showed reduced expression of genes associated with IgE class switching and plasma cell differentiation. Conclusion CCR6 expression on B cells is required for IgE production following tick sensitization. Our findings suggest that CCR6 signaling promotes IgE class switching and plasma cell differentiation, providing new mechanistic insight into AGS. Funding Source NIH R01 AI172112 Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)