Developing vaccines based on lipid antigens requires defining appropriate adjuvants. Whereas CD1d is constitutively expressed on antigen presenting cells (APC), CD1a, CD1b and CD1c are not. Therefore, one desired property of adjuvants would be to induce group 1 CD1 protein expression. Activation of some Toll-Like Receptors (TLR) induces group 1 CD1 protein expression on human monocytes, converting myeloid precursors into competent APC. Indeed, ligands of TLR2/1 (19 kDa lipoprotein, Pam₃CSK₄), TLR2/6 (Malp-2, Pam₂CSK₄), TLR4 (LPS) and TLR5 (flagellin) trigger expression of CD1b. In the context of Mycobacterium tuberculosis and Borrelia burgdorferi infections, TLR2-mediated induction of group 1 CD1 protein expression was found to be caused by the release of a soluble factor identified as the cytokine IL1β.

Synthetic monophosphoryl lipid A (MPLA), a nontoxic derivative of the endotoxin lipopolysaccharide, has been approved by the USDA as the first TLR agonist for use as a vaccine adjuvant (MPL®), based on its ability to direct adaptive immune responses with little toxicity. The latter has been associated with a bias toward TRIF signaling and low or no production of mature IL1β. Surprisingly, we found that MPLA is able to induce the expression of CD1a, measured as a surrogate of the group 1 CD1 proteins. Moreover, CD1a expression was inhibited by treating monocytes by Z-VAD-FMK, a potent inhibitor of caspase-1, the enzyme required for the cleavage of pro-IL1β into the mature form. Z-VAD-FMK treatment concomitantly reduced the production of IL1β measured in the cell lysate, although we do not know at this stage whether it is pro- or mature IL1β.

Altogether, our data show that MPLA induces group 1 CD1 protein expression on APC by a mechanism that is under investigation, and would be appropriate for development as an adjuvant to be incorporated in vaccines made of lipid antigens.