Interferon gamma licensing of human dendritic cells in T-helper-independent CD8+ alloimmunity.
The high frequency of allogeneic reactive CD8(+) T cells in human and their resistance to immunosuppression might be one of the reasons why successful tolerance-inducing strategies in rodents have failed in primates. Studies on the requirement for T-helper cells in priming CD8(+) T-cell responses have led to disparate findings. Recent studies have reported CD8(+)-mediated allograft rejection independently of T-helper cells; however, the mechanisms that govern the activation of these T cells are far from being elucidated. In this study, we demonstrated that lipopolysaccharide-treated dendritic cells (DCs) were able to induce proliferation and cytotoxic activity of allogeneic CD8(+) T cells independently of CD4(+) T cells, while adding mycophenolic acid (MPA) to LPS abolished this capacity and resulted in anergic CD8(+) T cells that secreted high levels of interleukin-4 (IL-4), IL-5, IL-10, and transforming growth factor-β. Interestingly, we demonstrated that MPA inhibited the LPS-induced synthesis of tumor necrosis factor-α, IL-12, and interferon-γ (IFN-γ) in DCs. Importantly, we found that adding exogenous IFN-γ to MPA restored both the synthesis of cytokines and the ability to activate CD8(+) T cells. However, adding IL-12 or tumor necrosis factor-α had no effect. These results suggest that IFN-γ has an important role in licensing DCs to prime CD4-independent CD8 allogeneic T cells via an autocrine loop.
Lemoine
Roxane
R
Unité Propre de Recherche de l'Enseignement Supérieur Equipe d'Accueil 4245 Cellules Dendritiques, Immunomodulation et Greffes, Unité Formation et de Recherch (UFR) de Médecine, Institut Fédératif de Recherche 136, Université François Rabelais, Tours, France. roxlem@orange.fr
Velge-Roussel
Florence
F
Herr
Florence
F
Felix
Romain
R
Nivet
Hubert
H
Lebranchu
Yvon
Y
Baron
Christophe
C
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D018920:Coculture Techniques; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008213:Lymphocyte Activation; D009173:Mycophenolic Acid / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D009173:Mycophenolic Acid