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 calcitrioldependent mechanisms. Herein, we report that murine DCs exposed to TLR3/TLR4 ligands upregulate their expression of 1α-hydroxylase, the enzyme that converts circulating 25(OH)D 3 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 1α-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. Keywords dendritic cells; TLR ligands; mucosal immune response; calcitriol
IntroductionIn mammals there are at least 12 members of the toll like receptor (TLR) family. These receptors not only recognize a number of specific components conserved among microorganisms, but are also capable of recognizing specific defensins as well as fragments of extracellular matrix proteins [1][2][3][4][5][6][7]. Since, the activation of macrophages or dendritic cells (DCs) through one or more of their TLRs enhances innate immunity and can modulate the subsequent development of antigen-specific adaptive immunity, some TLR ligands have been used as adjuvants in vaccine formulations administered parenterally to augment systemic immune responses [8][9][10][11]. Specific TLR ligands have been reported to promote the induction of both systemic and mucosal immune responses when co-administered with antigen intranasally [9][10][11][12].*Corresponding author. Address: Department of Pathology, University of Utah Medical School, 30 North 1900 East, Salt Lake City, UT 84132, USA; Phone: 1-801-585-1522; Fax: 1-801-581-8946; e-mail: elena.enioutina@path.utah.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Author ManuscriptVaccine. Author manuscript; available in PMC 2009 January 30.
Published in final edited form as:Vaccine. We have previously demonstrated that the subcutaneous or intradermal imm...