Antigen-activated T cells induce IL-12p75 production from dendritic cells in an IFN-γ-independent manner.
The addition of IL-12p75 to naïve CD4(+) T cells promotes their differentiation towards a TH1-type cytokine pattern. Dendritic cells stimulated by LPS generate IL-12p75, but only if the environment also contains IFN-γ. Thus, it appears that IFN-γ is needed to start the response that will result in further production of IFN-γ. We previously reported that paradoxically DCs produce IL-12p75 only after engaging primed, but not naïve T cells. This study examines the mechanism by which primed T cells trigger IL-12p75 secretion and asks whether this induction is also dependent on the presence of IFN-γ. Here, we show that, in contrast to LPS, primed T cells induce IL-12p75 in an IFN-γ-independent manner. Addition of rIFN-γ to cocultures of naïve T cells with DCs did not induce IL-12p75. Moreover, antigen-activated CD4(+) T cells from wild type or IFN-γ-deficient mice both initiated IL-12p75 production from DCs. Surprisingly, we found that synergies between three T-cell-derived factors - CD40 Ligand, IL-4 and GM-CSF - were necessary and sufficient for IL-12p75 production. These results suggest that there are at least two distinct pathways for IL-12p75 production in vivo. Furthermore, the T-cell-dependent pathway of IL-12p75 production employs molecules that are not classically associated with a TH1-type response.
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0420, USA. kabdi@niaid.nih.gov
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Singh
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000276:immunology*; D018664:Interleukin-12 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018089:Superantigens / Q000276:immunology
D019013:CD40 Antigens; D008024:Ligands; D018089:Superantigens; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor