TLR ligands that stimulate the metabolism of vitamin D3 in activated murine dendritic cells can function as effective mucosal adjuvants to subcutaneously administered vaccines

Vaccine. 2008 Jan 30;26(5):601-13. doi: 10.1016/j.vaccine.2007.11.084. Epub 2007 Dec 26.

Abstract

Cathelicidin production by human myeloid cells stimulated through toll-like receptor (TLR) 2/1, the migration of human CD8+ T cells to inflamed skin sites, and the ability of murine dendritic cells (DCs) to migrate from skin sites of vaccination to mucosal lymphoid organs all occur via calcitriol-dependent mechanisms. Herein, we report that murine DCs exposed to TLR3/TLR4 ligands upregulate their expression of 1 alpha-hydroxylase, the enzyme that converts circulating 25(OH)D3 to calcitriol, the active form of vitamin D3. TLR3/TLR4 ligands injected subcutaneously affect DC migration in vivo, allowing their trafficking to both draining and non-draining systemic and mucosal lymphoid organs. Subcutaneously delivered vaccines containing TLR3/TLR4 ligands and antigen stimulate the induction of both systemic and mucosal immune responses. Vaccines containing TLR9 ligands fail to stimulate 1 alpha-hydroxylase protein expression, are incapable of redirecting DC migration into Peyer's patches and do not induce mucosal immune responses. These findings support a hypothesis that active metabolites of vitamin D3 produced locally are able to affect various aspects of innate and acquired immune responses.

Publication types

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

MeSH terms

  • Animals
  • Bacterial Proteins / administration & dosage
  • Bacterial Proteins / immunology
  • Calcitriol / metabolism*
  • Cell Movement
  • Cells, Cultured
  • Cholecalciferol / metabolism*
  • Dendritic Cells / physiology*
  • Hydrolases / metabolism
  • Immunity, Mucosal
  • Injections, Subcutaneous
  • Ligands
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Transgenic
  • Peyer's Patches / immunology
  • Receptors, Antigen, T-Cell / deficiency
  • Receptors, Antigen, T-Cell / genetics
  • Toll-Like Receptor 3 / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • Up-Regulation
  • Vaccination*

Substances

  • Bacterial Proteins
  • Ligands
  • Receptors, Antigen, T-Cell
  • Toll-Like Receptor 3
  • Toll-Like Receptor 4
  • CRM197 (non-toxic variant of diphtheria toxin)
  • Cholecalciferol
  • Hydrolases
  • Calcitriol