title: Ectopic T-bet expression licenses dendritic cells for IL-12-independent priming of type 1 T cells in vitro.
abstract: T-bet (TBX21) is a transcription factor required for the optimal development of type 1 immune responses. Although initially characterized for its intrinsic role in T cell functional polarization, endogenous T-bet may also be critical to the licensing of type 1-biasing APCs. Here, we investigated whether human dendritic cells (DC) genetically engineered to express high levels of T-bet (i.e., DC.Tbet) promote superior type 1 T cell responses in vitro. We observed that DC.Tbet were selective activators of type 1 effector T cells developed from the naive pool of responder cells, whereas DC.Tbet and control DC promoted type 1 responses equitably from the memory pool of responder cells. Naive T cells primed by (staphylococcal enterotoxin B or tumor-associated protein-loaded) DC.Tbet exhibited an enhancement in type 1- and a concomitant reduction in Th2- and regulatory T cell-associated phenotype/function. Surprisingly, DC.Tbets were impaired in their production of IL-12 family member cytokines (IL-12p70, IL-23, and IL-27) when compared with control DC, and the capacity of DC.Tbet to preferentially prime type 1 T cell responses was only minimally inhibited by cytokine (IL-12p70, IL-23, IFN-gamma) neutralization or receptor (IL-12Rbeta2, IL-27R) blockade during T cell priming. The results of transwell assays suggested the DC.Tbet-mediated effects are predominantly the result of direct DC-T cell contact or their close proximity, thereby implicating a novel, IL-12-independent mechanism by which DC.Tbets promote improved type 1 functional polarization from naive T cell responders. Given their superior type 1 polarizing capacity, DC.Tbet may be suitable for use in vaccines designed to prevent/treat cancer or infectious disease.
authors.affiliation: Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lipscomb
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Taylor
authors.forename: Christina
authors.initials: C
authors.lastname: Goldbach
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wesa
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Storkus
mesh_terms: D015153:Blotting, Western; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D018664:Interleukin-12 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D008856:Microscopy, Fluorescence; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12