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Abstract
Abstract Successful induction of pathogen-specific humoral B cell memory responses depends upon help from CD4+ T cells. We find that invariant natural killer T (iNKT) cells, glycolipid-specific, CD1d-restricted innate lymphocytes, can provide both cognate (direct) and noncognate (or indirect) helper signals to enhance B cell humoral responses. In fact, a subset of iNKT cells, termed iNKT follicular helper cells, are the cells which specifically act to promote germinal centers, facilitate optimal B cell memory, and plasma cell differentiation. While both cognate and noncognate iNKT cell help induce class-switched, antigen-specific humoral immune responses, only noncognate iNKT cell help drives formation of humoral memory and plasma cell development. We find that differences in the strength of the TcR signal received by iNKT cells, very early effector cytokine production by iNKT cells, T follicular helper cells, and T follicular regulatory cells all contribute to the observed differences in the ultimate humoral outcome. These findings help to identify the optimal requirements for iNKT induction of humoral memory, which has important implications for the application of glycolipid molecules as humoral adjuvants.
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