IgD Activates an Ancestral Galectin-9-CD44-Dependent Protective Pathway That Uncouples Th2 Immunity From Th2 Inflammation

Immunoglobulin D (IgD) is an ancestral antibody class that emerged in lower vertebrates before the inception of specific Fc receptors. Besides serving as a B cell antigen receptor, IgD mediates enigmatic fluid-phase functions after its release by plasma cells positioned at mucosal and systemic sites of antigen entry. We found that some plasma cells released IgD during both pre-immune and post-immune antibody responses. Basophils captured secreted IgD through a mechanism involving interaction of IgD with the galactose-binding lectin galectin-9 and CD44, a galectin-9 receptor with immunoregulatory function. Cross-linking of soluble IgD by cognate antigen triggered basophil secretion of interleukin-4 (IL-4), IL-5 and IL-13 as well as expansion of IL-4-expressing T follicular helper cells. The resulting T helper type-2 (Th2) response enhanced B cell production of high-affinity IgG1 antibodies through a basophil-regulated germinal center pathway that required IgD, CD44 and galectin-9 but not FceRI, a degranulation-inducing IgE receptor involved in allergy. Despite enhancing IgE production, IgD mitigated IgE-mediated basophil degranulation and allergy induction through a mechanism possibly involving galectin-9 and CD44, two known FceRI signaling inhibitors. Thus, higher vertebrates may retain an ancestral IgD secretory pathway to maximize antigen clearance via induction of non-inflammatory Th2 responses.