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.
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Authors | Weiguo Cui, Nikhil S Joshi, Ying Liu, Hailong Meng, Steven H Kleinstein, Susan M Kaech |
Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 192
Issue 9
Pg. 4221-32
(May 01 2014)
ISSN: 1550-6606 [Electronic] United States |
PMID | 24659688
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adjuvants, Immunologic
- Ligands
- Lipid A
- Lipopolysaccharides
- Tlr4 protein, mouse
- Toll-Like Receptor 4
- monophosphoryl lipid A
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Topics |
- Adjuvants, Immunologic
(pharmacology)
- Animals
- CD8-Positive T-Lymphocytes
(cytology, drug effects, immunology)
- Cell Differentiation
(drug effects)
- Immunologic Memory
(drug effects, immunology)
- Ligands
- Lipid A
(analogs & derivatives, immunology)
- Lipopolysaccharides
(immunology)
- Lymphocyte Activation
(drug effects, immunology)
- Mice
- Mice, Transgenic
- Oligonucleotide Array Sequence Analysis
- Toll-Like Receptor 4
(agonists)
- Vaccination
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