TLR4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A Differentially Regulate Effector and Memory CD8+ T Cell Differentiation

Abstract

Vaccines formulated with nonreplicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in Ab production has been well studied, but how they influence memory CD8+ T cell differentiation remains poorly defined. In this study we implemented dendritic cell–mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8+ T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8+ T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8+ T cells died during contraction, generating a larger pool of memory cells. Surprisingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8+ T cells, but it also promoted their terminal differentiation and contraction; thus, fewer memory CD8+ T cells formed, and MPLA-primed animals were less protected against secondary infection compared with those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells aligned closer with terminal effector CD8+ T cells. Lastly, we demonstrated that the LPS-TLR4–derived “pro-memory” signals were MyD88, but not Toll/IL-1R domain–containing adapter inducing IFN-β, dependent. This study reveals the influential power of adjuvants on the quantity and quality of CD8+ T cell memory, and that attention to adjuvant selection is crucial because boosting effector cell expansion may not always equate with more memory T cells or greater protection.