title: Vaccination Produces CD4 T Cells with a Novel CD154-CD40-Dependent Cytolytic Mechanism.
abstract: The discovery of new vaccines against infectious diseases and cancer requires the development of novel adjuvants with well-defined activities. The TLR4 agonist adjuvant GLA-SE elicits robust Th1 responses to a variety of vaccine Ags and is in clinical development for both infectious diseases and cancer. We demonstrate that immunization with a recombinant protein Ag and GLA-SE also induces granzyme A expression in CD4 T cells and produces cytolytic cells that can be detected in vivo. Surprisingly, these in vivo CTLs were CD4 T cells, not CD8 T cells, and this cytolytic activity was not dependent on granzyme A/B or perforin. Unlike previously reported CD4 CTLs, the transcription factors Tbet and Eomes were not necessary for their development. CTL activity was also independent of the Fas ligand-Fas, TRAIL-DR5, and canonical death pathways, indicating a novel mechanism of CTL activity. Rather, the in vivo CD4 CTL activity induced by vaccination required T cell expression of CD154 (CD40L) and target cell expression of CD40. Thus, vaccination with a TLR4 agonist adjuvant induces CD4 CTLs, which kill through a previously unknown CD154-dependent mechanism.
authors: Infectious Disease Research Institute, Seattle, WA 98102; Department of Global Health, University of Washington, Seattle, WA 98105; and PAI Life Sciences, Seattle, WA 98102.
authors: Rhea N
authors: RN
authors: Coler
authors: Infectious Disease Research Institute, Seattle, WA 98102;
authors: Thomas
authors: T
authors: Hudson
authors: Infectious Disease Research Institute, Seattle, WA 98102;
authors: Sean
authors: S
authors: Hughes
authors: Infectious Disease Research Institute, Seattle, WA 98102;
authors: Po-Wei D
authors: PW
authors: Huang
authors: Infectious Disease Research Institute, Seattle, WA 98102;
authors: Elyse A
authors: EA
authors: Beebe
authors: Infectious Disease Research Institute, Seattle, WA 98102; Department of Global Health, University of Washington, Seattle, WA 98105; and Mark.orr@idri.org.
authors: Mark T
authors: MT
authors: Orr
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000276:immunology*; D003603:Cytotoxins / Q000276:immunology; D053222:Fas Ligand Protein / Q000276:immunology; D053804:Granzymes / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D003603:Cytotoxins; C491198:Eomes protein, mouse; D053222:Fas Ligand Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D020825:T-Box Domain Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D023201:CD40 Ligand; D053804:Granzymes; C000597315:granzyme A, mouse