title: Multiple innate signaling pathways cooperate with CD40 to induce potent, CD70-dependent cellular immunity.
abstract: We have previously shown that Toll-like receptor (TLR) agonists cooperate with CD40 to generate CD8 T cell responses exponentially larger than the responses generated with traditional vaccine formulations. We have also shown that combined TLR agonist/anti-CD40 immunization uniquely induces the upregulation of CD70 on antigen bearing dendritic cells (DCs). In contrast, immunization with either a TLR agonist or a CD40 stimulus alone does not significantly increase CD70 expression on DCs. Furthermore, the CD8(+) T cell response generated by combined TLR agonist/anti-CD40 immunization is dependent on the expression of CD70 by DCs, as CD70 blockade following immunization dramatically decreases the CD8 T cell response. Here we show that other innate pathways, independent of the TLRs, can also cooperate with CD40 to induce potent, CD70 dependent, CD8 T cell responses. These innate stimuli include Type I IFN (IFN) and alpha-galactosylceramide (alphaGalCer) or aC-GalCer, glycolipids that are presented by a nonclassical class I MHC molecule, CD1d, and are able to activate NKT cells. Furthermore, this combined IFN/anti-CD40 immunization generates protective memory against bacterial challenge with Listeria monocytogenes. Together these data indicate the importance of assessing CD70 expression on DCs as a marker for the capacity of a given vaccine formulation to potently activate cellular immunity. Our data indicate that optimal induction of CD70 expression requires a coordinated stimulation of both innate (TLR, IFN, alphaGalCer) and adaptive (CD40) signaling pathways.
authors.affiliation: Integrated Department of Immunology, University of Colorado Denver, Aurora, CO 80206, United States.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: McWilliams
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Sanchez
authors.forename: Catherine
authors.initials: C
authors.lastname: Haluszczak
authors.forename: Laurent
authors.initials: L
authors.lastname: Gapin
authors.forename: Ross M
authors.initials: RM
authors.lastname: Kedl
mesh_terms: D000818:Animals; D053282:CD27 Ligand / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D007156:Immunologic Memory; D008089:Listeria monocytogenes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction
chemical_list: D053282:CD27 Ligand; D019013:CD40 Antigens