Invariant natural killer T (iNKT) cells act as cellular adjuvants by providing co-stimulation to antigen presenting cells (APCs) upon recognition of the glycolipid, a-galactosylceramide (aGalCer), in the context of CD1d. Thus, when aGalCer is co-administered with soluble peptide antigens, iNKT cells are able to license APCs, thereby enhancing the immunogenic presentation of peptide:MHC complexes to CD8+ T cells, leading to increased antigen-specific immunity. However, in mice, iNKT cells represent ~1% of all circulating T cells while in humans iNKT cells are of a much lower frequency (~0.01 - 0.1% of all circulating T cells). Whether this significant discrepancy between mouse and human iNKT cell frequency will limit their capacity to act as cellular adjuvants in clinical applications is unknown.

Another innate-like T cell population, mucosal associated invariant T (MAIT) cells, has recently been recently described to play key roles in both sterile and non-sterile pathologies. Indeed, MAIT cells can rapidly exert effector functions upon TCR dependent recognition of riboflavin metabolites, presented in the context of MR1, or in a TCR independent manner via cytokines. Importantly, and in contrast to iNKT cells, they represent an abundant population of circulating human T cells (1-10%). Using novel chemistry, we have generated synthetic MAIT cell agonists to determine whether, similarly to iNKT cells, MAIT cells can be harnessed as immunotherapeutic adjuvants.