Follicular Helper NKT Cells Induce Limited B Cell Responses and Germinal Center Formation in the Absence of CD4+ T Cell Help

Abstract

B cells require MHC class II (MHC II)-restricted cognate help and CD40 engagement by CD4+ T follicular helper (TFH) 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 CXCR5hiprogrammed death-1hiICOShiBcl-6hi TFH 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 iNKTFH 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 iNKTFH and CD4+ TFH cells display distinct helper features, consistent with the notion that these two cell subsets play nonredundant functions throughout immune responses.

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

“…In the spleen and LNs of immunized mice, the frequency of iNKT FH cells has been shown to be comparable with that of T FH cells induced by TD Ags [54,55]. Furthermore, iNKT FH cells have also been detected in human tonsils, and this finding implied that iNKT FH cells are spontaneously induced by environmental Ags in humans [54].…”

“…Moreover, iNKT FH cells promote considerably rapid GC formation (within 3 days post immunization) as compared with T FH cells, which promote GC formation 10 days post immunization with protein Ags. However, the GCs that are induced by iNKT FH -cell help are short-lived and do not produce longlived plasma cells and memory responses [54][55][56]. Thus, the specific characteristics of humoral responses that are elicited with the help of cognate iNKT FH cells are distinct from the characteristics of previously described TI and TD B-cell responses and have prompted the new definition of TD type 2 responses [56] (Fig.…”

“…Consistent with their ability to provide help to cognate B cells, iNKT cells have recently been found to adopt the T FH -cell phenotype [54,55] and localize within GCs [54] in mice immunized with particulated or even soluble αGalCer. In the spleen and LNs of immunized mice, the frequency of iNKT FH cells has been shown to be comparable with that of T FH cells induced by TD Ags [54,55]. Furthermore, iNKT FH cells have also been detected in human tonsils, and this finding implied that iNKT FH cells are spontaneously induced by environmental Ags in humans [54].…”

“…Moreover, iNKT FH cells promote considerably rapid GC formation (within 3 days post immunization) as compared with T FH cells, which promote GC formation 10 days post immunization with protein Ags. However, the GCs that are induced by iNKT FH -cell help are short-lived and do not produce longlived plasma cells and memory responses [54][55][56] [38,56]. In CD4 + T-cell-deficient mice, iNKT FH cells expanded more than in Th-cell-sufficient mice [55], suggesting that in physiological conditions the expansion of iNKT FH cells may be limited by the competition with T FH cells and/or by the suppression exerted by a specialized subset of Treg cells that have been found infiltrating GCs [57,58].…”

“…However, the GCs that are induced by iNKT FH -cell help are short-lived and do not produce longlived plasma cells and memory responses [54][55][56] [38,56]. In CD4 + T-cell-deficient mice, iNKT FH cells expanded more than in Th-cell-sufficient mice [55], suggesting that in physiological conditions the expansion of iNKT FH cells may be limited by the competition with T FH cells and/or by the suppression exerted by a specialized subset of Treg cells that have been found infiltrating GCs [57,58].It has been observed, however, that immunization of WT mice with the haptenated protein 4-hydroxy-3-nitrophenylacetylkeyhole limpet hemocyanin (NP-KLH) mixed with αGalCer elicits class-switched Ab responses that require both CD1d expression on B cells and the presence of Th cells [34,59]. At variance with the described examples of cognate and noncognate iNKT-cell help [38,39,54], the induction of B-cell responses by this particular Ag model does not require CD40L and CD1d expression on iNKT cells and DCs, respectively [60,61].…”