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: Michael W Lipscomb, Lu Chen, Jennifer L Taylor, Christina Goldbach, Simon C Watkins, Pawel Kalinski, Lisa H Butterfield, Amy K Wesa, Walter J Storkus
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 11 Pg. 7250-8 (Dec 01 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 19915058 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Interleukin-12

Topics

• Blotting, Western
• Cell Communication (immunology)
• Cell Differentiation (immunology)
• Cytokines (biosynthesis, immunology)
• Dendritic Cells (immunology)
• Enzyme-Linked Immunosorbent Assay
• Flow Cytometry
• Humans
• Interleukin-12 (immunology)
• Lymphocyte Activation (immunology)
• Microscopy, Fluorescence
• Reverse Transcriptase Polymerase Chain Reaction
• T-Box Domain Proteins (biosynthesis, genetics, immunology)
• Th1 Cells (cytology, immunology)