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CD1d-restricted invariant NKT (iNKT) cells boost humoral immunity to T-dependent Ags that are coadministered with the CD1d-binding glycolipid Ag α-galactosylceramide (α-GC). Observations that mice lacking iNKT cells have decaying Ab responses following vaccination have led to the hypothesis that iNKT cells express plasma cell (PC) survival factors that sustain specific Ab titers. Bone marrow chimeric mice in which the entire hematopoietic compartment or iNKT cells selectively lacked BAFF, a proliferation-inducing ligand (APRIL), or both BAFF and APRIL were created and immunized with nitrophenol hapten-conjugated keyhole limpet hemocyanin adsorbed to Imject aluminum hydroxide-containing adjuvant or mixed with α-GC. In comparison with BAFF- or APRIL-sufficient bone marrow chimeras, absence of hematopoietic compartment- and iNKT-derived BAFF and APRIL was associated with rapidly decaying Ab titers and reduced PC numbers. The iNKT cell-derived BAFF or APRIL assumed a greater role in PC survival when α-GC was used as the adjuvant for immunization. These results show that iNKT cell-derived BAFF and APRIL each contribute to survival of PCs induced by immunization. This study sheds new light on the mechanisms through which iNKT cells impact humoral immunity and may inform design of vaccines that incorporate glycolipid adjuvants.

Alum-based adjuvants facilitate vaccine-driven humoral immunity, but their mechanism of action remains poorly understood. Herein, we report that lack of type II NKT cells is associated with intact, mature B cells but dampened humoral immunity following immunization with Alum-adsorbed T-dependent antigen. Type II NKT cells facilitated production of IL-4, IL-5, IL-10, IL-13, and antibody by LN and splenocyte cultures following Alum/antigen administration in vivo and antigen restimulation in vitro. Addition of IL-4 and IL-5 to type II NKT-deficient cultures restored in vitro antibody production. Intracellular staining revealed that Alum-primed type II NKT cells coordinated IL-4 secretion by T cells. Alum did not significantly affect CD1d expression in vivo, but addition of CD1d-blocking mAb diminished cytokine production and in vitro antibody production. Type II NKT cells therefore function as part of the Alum-sensing apparatus and in a CD1d-dependent manner, facilitate T(H)2-driven humoral immunity. This may have important consequences for understanding the mechanism of action of Alum-containing vaccines.