Cholera toxin activates nonconventional adjuvant pathways that induce protective CD8 T-cell responses after epicutaneous vaccination.
The ability to induce humoral and cellular immunity via antigen delivery through the unbroken skin (epicutaneous immunization, EPI) has immediate relevance for vaccine development. However, it is unclear which adjuvants induce protective memory CD8 T-cell responses by this route, and the molecular and cellular requirements for priming through intact skin are not defined. We report that cholera toxin (CT) is superior to other adjuvants in its ability to prime memory CD8 T cells that control bacterial and viral challenges. Epicutaneous immunization with CT does not require engagement of classic toll-like receptor (TLR) and inflammasome pathways and, surprisingly, is independent of skin langerin-expressing cells (including Langerhans cells). However, CT adjuvanticity required type-I IFN sensitivity, participation of a Batf3-dependent dendritic cell (DC) population and engagement of CT with suitable gangliosides. Chemoenzymatic generation of CT-antigen fusion proteins led to efficient priming of the CD8 T-cell responses, paving the way for development of this immunization strategy as a therapeutic option.
Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis MN 55414, USA.
Irlanda
I
Olvera-Gomez
Sara E
SE
Hamilton
Zhengguo
Z
Xiao
Carla P
CP
Guimaraes
Hidde L
HL
Ploegh
Kristin A
KA
Hogquist
Liangchun
L
Wang
Stephen C
SC
Jameson
D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000279:Administration, Cutaneous; D000818:Animals; D000941:Antigens / Q000276:immunology; D000954:Antigens, Surface / Q000378:metabolism; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000008:administration & dosage* / Q000276:immunology*; D005677:G(M1) Ganglioside / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects; D007370:Interferon Type I / Q000276:immunology; D037181:Lectins, C-Type / Q000378:metabolism; D037241:Mannose-Binding Lectins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D014611:Vaccination
D000276:Adjuvants, Immunologic; D000941:Antigens; D000954:Antigens, Surface; D050976:Basic-Leucine Zipper Transcription Factors; C408982:CPG-oligonucleotide; C498497:Cd207 protein, mouse; D007370:Interferon Type I; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D009838:Oligodeoxyribonucleotides; D012097:Repressor Proteins; C533289:SNFT protein, mouse; D051193:Toll-Like Receptors; D005677:G(M1) Ganglioside; D002772:Cholera Toxin