IL-6 inhibits the tolerogenic function of CD8 alpha+ dendritic cells expressing indoleamine 2,3-dioxygenase.
The outcome of dendritic cell (DC) presentation of tumor and/or self peptides, including P815AB (a tumor peptide of murine mastocytoma cells) and NRP-A7 (a synthetic peptide mimotope recognized by diabetogenic T cells), may depend on a balance between the activities of immunogenic (CD8alpha(-)) and tolerogenic (CD8alpha(+)) DC. By virtue of their respective actions on CD8(-) and CD8(+) DC, IL-12 and IFN-gamma have functionally opposing effects on peptide presentation by the CD8(-) DC subset, and IFN-gamma-activated CD8(+) DC mediate tolerogenic effects that prevail over the adjuvant activity of IL-12 on CD8(-) DC. We have previously shown that CD40 ligation abrogates the tolerogenic potential of CD8(+) DC, an effect associated with an impaired capacity of the CD40-modulated and IFN-gamma-treated DC to degrade tryptophan and initiate T cell apoptosis in vitro. We report here that IL-6 may both replace (upon administration of the recombinant cytokine) and mediate (as assessed by the use of neutralizing Abs) the effect of CD40 ligation in ablating the tolerogenic activity of CD8(+) DC. The activity of IL-6 includes down-regulation of IFN-gammaR expression in the CD8(+) DC subset and correlates to a reduced ability of these cells to metabolize tryptophan and initiate T cell apoptosis in vitro.
Grohmann
U
U
Department of Experimental Medicine, University of Perugia, Via del Giochetto, I-06122 Perugia, Italy.
Fallarino
F
F
Bianchi
R
R
Belladonna
M L
ML
Vacca
Carmine
C
Orabona
C
C
Uyttenhove
C
C
Fioretti
M C
MC
Puccetti
P
P
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D016827:CD8 Antigens / Q000096:biosynthesis*; D002478:Cells, Cultured; D002999:Clone Cells; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D004790:Enzyme Induction / Q000276:immunology; D007106:Immune Sera / Q000494:pharmacology; D007108:Immune Tolerance / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000276:immunology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000096743:Interferon gamma Receptor
D019013:CD40 Antigens; D016827:CD8 Antigens; D007106:Immune Sera; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D015850:Interleukin-6; D017471:Receptors, Interferon; D014366:Tryptophan Oxygenase; D000096743:Interferon gamma Receptor; C431698:CD8alpha antigen