IL-15 promotes IL-12 production by human monocytes via T cell-dependent contact and may contribute to IL-12-mediated IFN-gamma secretion by CD4+ T cells in the absence of TCR ligation.
At inflammatory sites, the number of activated bystander T cells exceeds that of Ag-activated T cells. We investigated whether IL-15, a monocyte-derived cytokine that shares several biologic activities with IL-2, may contribute to bystander T cell activation in the absence of IL-2 and triggering Ag. The addition of IL-15 to cocultures of monocytes and T cells stimulates CD4+ but not CD8+ T cells to produce IFN-gamma. IFN-gamma production requires endogenous IL-12, the production of which in turn is dependent upon CD40/CD154 interactions between CD4+ T cells and monocytes. Indeed, non-TCR-activated CD4+ but not CD8+ T cells express significant levels of CD154. IL-15 may enhance IFN-gamma in this system by up-regulating CD40 expression on monocytes and IL-12Rbeta1 expression on CD4+ T cells. Conversely, using neutralizing anti-IL-15 mAb, we show that the ability of IL-12 to augment IFN-gamma secretion is partly mediated by endogenous IL-15. Finally, in the absence of monocytes, a synergistic effect between exogenous IL-12 and IL-15 is necessary to induce IFN-gamma production by purified CD4+ T cells, while IL-15 alone induces T cell proliferation. It is proposed that this codependence between IL-12 and IL-15 for the activation of inflammatory T cells may be involved in chronic inflammatory disorders that are dominated by a Th1 response. In such a response, a self-perpetuating cycle of inflammation is set forth, because IL-15-stimulated CD4+ T cells may activate monocytes to release IL-12 that synergizes with IL-15 to induce IL-12 response and IFN-gamma production.
University of Montreal, Allergy Research Laboratory, Louis-Charles Simard Research Center, Notre-Dame Hospital, Canada.
M N
MN
Avice
C E
CE
Demeure
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G
Delespesse
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M
Rubio
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Armant
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Sarfati
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000941:Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019013:CD40 Antigens / Q000502:physiology; D023201:CD40 Ligand; D002450:Cell Communication / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D019409:Interleukin-15 / Q000494:pharmacology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology; D009000:Monocytes / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism*
D000276:Adjuvants, Immunologic; D000941:Antigens; D019013:CD40 Antigens; D019409:Interleukin-15; D008024:Ligands; D008562:Membrane Glycoproteins; D011948:Receptors, Antigen, T-Cell; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma