T-bet is required for optimal production of IFN-gamma and antigen-specific T cell activation by dendritic cells.
IFN-gamma is well known as the signature cytokine of CD4+ T helper 1, CD8+, and natural killer cells, but recent studies demonstrate that antigen-presenting cells, in particular dendritic cells (DCs), are another potent source for this proinflammatory cytokine. T-bet, a transcription factor that controls IFN-gamma expression in CD4+ T cells, was reported recently to be expressed in human monocytes and myeloid DCs. In this study we investigate the role of T-bet in this important cell type. The development, differentiation, and activation of bone marrow and splenic DCs were unimpaired in mice lacking T-bet. However, T-bet was essential for the optimal production of IFN-gamma by both CD8alpha+ and CD8alpha- DCs. T-bet-deficient DCs were significantly impaired in their capacity to secrete IFN-gamma after both stimulation with IL-12 alone or in combination with IL-18. Further, T-bet-/- DCs were impaired in their ability to activate the T helper 1 program of adoptively transferred antigen-specific T cells in vivo. The rapid up-regulation of T-bet by IFN-gamma in DCs coupled with a function for DC-derived IFN-gamma in T cell activation may constitute a positive feedback loop to maximize type 1 immunity.
Lugo-Villarino
Geanncarlo
G
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115-6017, USA.
Maldonado-Lopez
Roberto
R
Possemato
Richard
R
Penaranda
Cristina
C
Glimcher
Laurie H
LH
D016475:3T3 Cells; D000818:Animals; D000941:Antigens / Q000378:metabolism; D015153:Blotting, Western; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology*; D015854:Up-Regulation; D000098815:T-bet Transcription Factor
D000941:Antigens; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor