title: The adjuvant effect of TLR agonists on CD4(+) effector T cells is under the indirect control of regulatory T cells.
abstract: TLR agonists have been suggested to directly impact Tregs, thereby enhancing or reversing their suppressive function. Here, in order to select TLR agonists leading to potent effector T-cell responses, while minimizing Treg inhibitory function, we used a model antigen, covalently linked to an inert delivery system, combined with a large panel of TLR agonists, for the immunization of mice with an attenuated/depleted or intact Treg subset. We observed that the negative modulation of effector CD4(+) T cells exerted by Tregs cannot be circumvented, whatever the TLR agonist used as adjuvant. To better understand the impact of TLR agonists on Tregs, we investigated (i) the TLR expression profile of highly purified CD4(+) Foxp3(+) Tregs, at steady state or subsequent to in vivo activation by TLR agonists and (ii) the Treg phenotype after in vivo and in vitro activation by TLR agonists. Our results demonstrate that TLR agonists, as single signal inducers, are not able to directly activate Tregs. The phenotypic Treg activation observed in vivo, following TLR administration, does not result from cross-talk with conventional T cells but is rather a consequence of the interaction with other immune cell type(s).
authors.affiliation: Department of Immunology, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Olivier
authors.forename: Alexander
authors.initials: A
authors.lastname: Sainz-Perez
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Laleh
authors.initials: L
authors.lastname: Majlessi
authors.forename: Claude
authors.initials: C
authors.lastname: Leclerc
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D015054:Zymosan / Q000494:pharmacology
chemical_list: D000276:Adjuvants, Immunologic; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007093:Imidazoles; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D051193:Toll-Like Receptors; D049452:Green Fluorescent Proteins; C489630:1018 oligonucleotide; D010047:Ovalbumin; D015054:Zymosan; D011070:Poly I-C; C402365:resiquimod