More help for B cells

Invariant natural killer T (iNKT) cells have previously been shown to provide cognate help for lipid-specific B cells. Two new studies provide further details of the long-term outcome of this help and describe a population of iNKT cells that resemble follicular helper T (T_FH) cells.

The lipid antigen α-galactosylceramide (αGalCer) binds to CD1d and is a potent activator of iNKT cells. To assess the outcome of cognate iNKT cell help for B cell responses, King et al. immunized B1-8 mice — in which ∼5% of B cells express a B cell receptor specific for the hapten NP (4-hydroxy-3-nitrophenylacetyl) — with the haptenated lipid antigen NP–αGalCer. NP–αGalCer induced the early formation of extrafollicular foci in the spleen and the expansion of NP-specific plasmablast populations. These responses are similar to those induced by T cell-independent antigens. However, in contrast with T cell-independent responses, the response to NP–αGalCer also involved germinal centre formation. Furthermore, NP–αGalCer induced modest antibody affinity maturation after two immunizations, whereas the T cell-independent antigen NP–Ficoll did not.

Interleukin-21 (IL-21) production by T_FH cells has an important role in T cell-dependent B cell responses. King et al. showed that iNKT cell-derived IL-21 has a role in the induction of early NP-specific IgG antibody production following immunization with NP–αGalCer. However, unlike T cell-dependent antigens, NP–αGalCer did not initiate an enhanced B cell memory response. So, these data suggest that cognate iNKT cell help for lipid-specific B cells induces a unique response that has characteristics of both T cell-dependent and T cell-independent B cell responses.

Chang et al. also found that immunization of mice containing hen egg lysozyme (HEL)-specific B cells with HEL conjugated to αGalCer (HEL–αGalCer) induced the rapid formation of germinal centres. Germinal centre formation was dependent on the expression of CD1d by the HEL-specific B cells, indicating that the help provided by iNKT cells was a result of cognate interactions between iNKT cells and B cells. Indeed, imaging studies showed that, in response to HEL–αGalCer immunization, HEL-specific B cells and iNKT cells formed stable interactions that promoted B cell activation.

Do these iNKT cells have a phenotype similar to that of T_FH cells? In αGalCer-immunized mice, ∼3% of iNKT cells isolated from the spleen and lymph nodes expressed high levels of the T_FH cell-associated markers CXCR5 and PD1. In addition, ∼10% of iNKT cells from human tonsil tissue were CXCR5^hiPD1^hi. Similarly to T_FH cell development, the development of 'follicular helper' iNKT cells in mice was shown to require the expression of the transcriptional repressor BCL-6, co-stimulation through CD28 and the presence of B cells. However, unlike T_FH cells, follicular helper iNKT cells developed independently of IL-21. Similarly to King et al., Chang et al. identified a role for IL-21 in the formation of germinal centre B cells and plasmablasts in response to HEL–αGalCer. However, follicular helper iNKT cells promoted only limited antibody affinity maturation and did not induce long-lived plasma cells.

So, these studies describe a population of iNKT cells with phenotypical and developmental characteristics similar to those of T_FH cells. Furthermore, iNKT cells can provide cognate help for germinal centre formation, although these germinal centres do not seem to support the formation of memory.