title: 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.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Weiguo
authors.initials: W
authors.lastname: Cui
authors.forename: Nikhil S
authors.initials: NS
authors.lastname: Joshi
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Hailong
authors.initials: H
authors.lastname: Meng
authors.forename: Steven H
authors.initials: SH
authors.lastname: Kleinstein
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects*; D007156:Immunologic Memory / Q000187:drug effects* / Q000276:immunology; D008024:Ligands; D008050:Lipid A / Q000031:analogs & derivatives / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D051197:Toll-Like Receptor 4 / Q000819:agonists; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D008024:Ligands; D008050:Lipid A; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C048436:monophosphoryl lipid A