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-FII) 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 alpha-galactosylceramide (alpha GalCer). We previously observed that immunization of mice lacking CD4(+) T cells (MHC II-/-) elicits specific IgG responses only when protein Ags are mixed with alpha GalCer. 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 alpha GalCer 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(hi)programmed death-1(hi)ICOS(hi)Bcl-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. The Journal of Immunology, 2012, 188: 3217-3222.