Cholera toxin activates nonconventional adjuvant pathways that induce protective CD8 T-cell responses after epicutaneous vaccination

Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):2072-7. doi: 10.1073/pnas.1105771109. Epub 2012 Jan 23.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adjuvants, Immunologic / metabolism*
  • Administration, Cutaneous
  • Animals
  • Antigens / immunology
  • Antigens, Surface / metabolism
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Cholera Toxin / administration & dosage*
  • Cholera Toxin / immunology*
  • G(M1) Ganglioside / immunology
  • Immunologic Memory / drug effects
  • Interferon Type I / immunology
  • Lectins, C-Type / metabolism
  • Mannose-Binding Lectins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Oligodeoxyribonucleotides / pharmacology
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects*
  • Signal Transduction / immunology
  • Toll-Like Receptors / immunology
  • Vaccination*


  • Adjuvants, Immunologic
  • Antigens
  • Antigens, Surface
  • Basic-Leucine Zipper Transcription Factors
  • CPG-oligonucleotide
  • Cd207 protein, mouse
  • Interferon Type I
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Oligodeoxyribonucleotides
  • Repressor Proteins
  • SNFT protein, mouse
  • Toll-Like Receptors
  • G(M1) Ganglioside
  • Cholera Toxin