T cells signaled by NF-kappa B- dendritic cells are sensitized not anergic to subsequent activation.
Paradoxically, while peripheral self-tolerance exists for constitutively presented somatic self Ag, self-peptide recognized in the context of MHC class II has been shown to sensitize T cells for subsequent activation. We have shown that MHC class II(+)CD86(+)CD40(-) DC, which can be generated from bone marrow in the presence of an NF-kappa B inhibitor, and which constitutively populate peripheral tissues and lymphoid organs in naive animals, can induce Ag-specific tolerance. In this study, we show that CD40(-) human monocyte-derived dendritic cells (DC), generated in the presence of an NF-kappa B inhibitor, signal phosphorylation of TCR zeta, but little proliferation or IFN-gamma in vitro. Proliferation is arrested in the G(1)/G(0) phase of the cell cycle. Surprisingly, responding T cells are neither anergic nor regulatory, but are sensitized for subsequent IFN-gamma production. The data indicate that signaling through NF-kappa B determines the capacity of DC to stimulate T cell proliferation. Functionally, NF-kappa B(-)CD40(-)class II(+) DC may either tolerize or sensitize T cells. Thus, while CD40(-) DC appear to "prime" or prepare T cells, the data imply that signals derived from other cells drive the generation either of Ag-specific regulatory or effector cells in vivo.
Thompson
Angus G
AG
Centre for Immunology and Cancer Research, Princess Alexandra Hospital, University of Queensland, Brisbane, Australia.
O'Sullivan
Brendan J
BJ
Beamish
Heather
H
Thomas
Ranjeny
R
D021581:Active Transport, Cell Nucleus; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology; D019013:CD40 Antigens / Q000032:analysis; D002478:Cells, Cultured / Q000276:immunology; D017635:Clonal Anergy; D003713:Dendritic Cells / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D006681:HLA-D Antigens / Q000032:analysis; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000172:deficiency*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000941:Antigens; D019013:CD40 Antigens; D006681:HLA-D Antigens; D007376:Interleukin-2; D008565:Membrane Proteins; D016328:NF-kappa B; D009570:Nitriles; D011518:Proto-Oncogene Proteins; C497593:RELB protein, human; D011948:Receptors, Antigen, T-Cell; D013450:Sulfones; D014157:Transcription Factors; C054979:antigen T cell receptor, zeta chain; D051841:Transcription Factor RelB; D007371:Interferon-gamma