Follicular helper NKT cells induce limited B cell responses and germinal center formation in the absence of CD4 + T cell help

B cells require MHC class II (MHC II)-restricted cognate help and CD40 engagement by CD4 + T follicular helper (T FH) cells to form germinal centers and long-lasting Ab responses. Invariant NKT (iNKT) cells are innate-like lymphocytes that jumpstart the adaptive immune response when activated by the CD1d-restricted lipid α-galactosylceramide (αGalCer). We previously observed that immunization of mice lacking CD4 + T cells (MHC II -/-) elicits specific IgG responses only when protein Ags are mixed with αGalCer. In this study, we investigated the mechanisms underpinning this observation. We find that induction of Ag-specific Ab responses in MHC II -/- mice upon immunization with protein Ags mixed with αGalCer requires CD1d expression and CD40 engagement on B cells, suggesting that iNKT cells provide CD1d-restricted cognate help for B cells. Remarkably, splenic iNKT cells from immunized MHC II -/- mice display a typical CXCR5 hiprogrammed death-1 hiICOS hiBcl-6 hi T FH phenotype and induce germinal centers. The specific IgG response induced in MHC II -/- mice has shorter duration than that developing in CD4-competent animals, suggesting that iNKT FH cells preferentially induce transient rather than long-lived Ab responses. Together, these results suggest that iNKT cells can be co-opted into the follicular helper function, yet iNKT FH and CD4 + T FH cells display distinct helper features, consistent with the notion that these two cell subsets play nonredundant functions throughout immune responses.