Microanatomical lipid niche controls intestinal memory B cell migration and effector function

Abstract

Abstract Enteric infections are a leading global burden, yet few oral vaccines elicit long-lasting immunity and prevent disease, likely due to our lack of understanding of intestinal immunological memory. Long-lived memory B cells can be rapidly reactivated to differentiate into plasma cells, thus further increasing antibody titers and mediating host protection. Such long-term protection requires memory B cells to migrate and persist in sub-anatomical niches within secondary lymphoid organs. While survival niches have been described for memory B cells in lymph nodes and spleen, no niche have been identified in mucosal lymphoid organs, such as Peyer’s patches (PPs). Here, we show that memory B cells require positioning in the PP subepithelial dome (SED) for maintenance and effector function. In PPs, memory B cells express the migratory receptors EBI2, which binds the oxysterol 7alpha, 25-hydroxycholesterol, and CCR6, which recognizes the chemokine CCL20. Both ligands are present in PPs and drive memory B cell migration in vitro. Conditional removal of EBI2 from memory B cells, either in a constitutive or acute fashion, alters their zonation in PPs, reduces their persistency, and impairs their antigen-specific response. While most memory B cells in PPs are IgA+, IgA B cell receptor expression is dispensable for memory B cell positioning in the SED. Using conditional mice for the enzymes generating the oxysterol gradient and cell specific Cre lines, we are currently mapping the cellular and metabolic requirements for EBI2 dependent memory B cell maintenance and effector function in PPs. Understanding the mechanisms for memory B cell persistence is fundamental to our understanding of the intestinal B cell memory response against pathogens. Previously supported by training grants from NIH (5 T32 AI 132152-2, 5 T32 AI 007349-29)