title: TLR ligands that stimulate the metabolism of vitamin D3 in activated murine dendritic cells can function as effective mucosal adjuvants to subcutaneously administered vaccines.
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.
authors.affiliation: Department of Pathology, University of Utah Medical School, 30 North 1900 East, Salt Lake City, UT 84132, USA. elena.enioutina@path.utah.edu <elena.enioutina@path.utah.edu>
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Enioutina
authors.forename: Diana
authors.initials: D
authors.lastname: Bareyan
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Daynes
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000276:immunology; D002117:Calcitriol / Q000378:metabolism*; D002465:Cell Movement; D002478:Cells, Cultured; D002762:Cholecalciferol / Q000378:metabolism*; D003713:Dendritic Cells / Q000502:physiology*; D006867:Hydrolases / Q000378:metabolism; D018928:Immunity, Mucosal; D007279:Injections, Subcutaneous; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D010581:Peyer's Patches / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D015854:Up-Regulation; D014611:Vaccination
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C028581:CRM197 (non-toxic variant of diphtheria toxin); D002762:Cholecalciferol; D006867:Hydrolases; D002117:Calcitriol