Adjuvants of Immunity: Harnessing Innate Immunity to Promote Adaptive Immunity

Since Jules Freund reported that crude mycobacterial extracts greatly promoted immune responses to antigens (1), the use of adjuvants has become a widespread, but poorly understood practice to promote T and B cell responses (2). Recent studies have begun to identify the chemical nature of several adjuvants and the cellular and molecular mechanisms of their long-elusive immunologi-cal effects. For example, conserved microbial structures are recognized by innate immunity receptors such as Toll-like receptors (TLRs) and the complement system, eliciting specific signaling cascades which, ultimately, result in enhancing and guiding T and B cell responses (for reviews, see references 3 and 4). Despite these considerable advances, the task of enhancing CD8 T cell priming to nonliving antigens, a major goal of vaccines against a range of infectious and cancer diseases, has eluded immunologists. In this issue, Gonzalez-Aseguino-laza and colleagues report that ␣-galactosylceramide (␣-Gal-Cer), a glycolipid originally extracted from marine sponges on the basis of its antitumor properties, promotes anti-malarial CD8 T cell immunity when coinjected with irradiated sporozoites (5). Unlike common microbial adjuvants, which signal through TLRs, ␣-GalCer functions as an anti-gen presented by CD1d to NKT cells expressing a conserved semi-invariant ␣␤ TCR (for a review, see reference 6). Like microbial adjuvants, however, ␣-GalCer activates dendritic cells (DCs), though it does so indirectly through the cognate interaction with CD1d-restricted ␣-GalCer–specific NKT cells. DCs are the antigen-presenting cell type that is central to adaptive immunity (7), and it is likely that the efficacy of different adjuvants can be explained by differences in signaling DCs to undergo the complex and coordinate maturation events that are required for efficient T cell priming. Here, we will review the emerging families of adjuvant-specific receptors, highlighting the recent recognition that specialized subsets lymphocytes, such as NKT cells, can function at the innate phase of immunity to promote and regulate adaptive immunity through interactions with DCs. Toll Receptors. Purified and synthetic components of microbial extracts exert potent adjuvant effects (for recent reviews, see references 8–10). These include a variety of lipids and glycolipids, such as mycolic acid, lipoarabi-nomannan (LAM), LPS, lipoteichoic acid and microbial GPI, polynucleotides, such as bacterial DNA (i.e., with un-methylated CpG sequences) and double stranded RNA (produced upon viral infection), lipoproteins, and even a conserved protein, flagellin, which enables bacterial motil-ity. Surprisingly, most of their effects now appear to be mediated by receptors belonging to a single gene family, the TLRs. Although Toll was …