Splenic MAdCAM-1+ marginal reticular cells deliver antibody-inducing signals and confer gut-homing properties to human marginal zone B cells (IRC5P.622)

Abstract

Abstract The splenic marginal zone (MZ) generates prompt antibody responses to blood-borne antigens through a unique subset of innate-like B cells that closely interact with poorly characterized stromal cells. We found that human MZ contained fibroblast-like marginal reticular cells (MRCs) that expressed MAdCAM-1 along with the stromal molecules Thy-1, thrombomodulin, ICAM-1 and VCAM-1, but lacked the endothelial molecules CD31, CD34 and von Willebrand factor. Similar to stromal lymphoid tissue organizers, MRCs up-regulated the adhesion molecules ICAM-1 and VCAM-1 in response to LT and TNF. Moreover, MRCs exposed to microbial TLR ligands, released the B cell-stimulating factors BAFF, APRIL and IL-6, which delivered survival, proliferation, class switching and plasma cell differentiation signals to MZ B cells. Plasma cells emerging from this pathway showed either T cell-dependent or T cell-independent ontogenetic features, and released IgM antibodies to conserved carbohydrate and lipid antigens shared by commensal and pathogenic bacteria. These antibodies decreased in splenectomized individuals. Finally, TLR-primed MRCs produced retinoic acid, which elicited MZ B cell expression of the gut-homing receptors a4b7 and CCR9. These findings indicate that MRCs have unique B cell-helper properties that could be harnessed to enhance vaccine-induced antibody responses systemically and perhaps at mucosal sites of antigen entry.