Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species.
Reduced capacity to produce ROS increases the severity of T cell-dependent arthritis in both mice and rats with polymorphisms in neutrophil cytosolic factor 1 (Ncf1) (p47phox). Since T cells cannot exert oxidative burst, we hypothesized that T cell responsiveness is downregulated by ROS produced by APCs. Macrophages have the highest burst capacity among APCs, so to study the effect of macrophage ROS on T cell activation, we developed transgenic mice expressing functional Ncf1 restricted to macrophages. Macrophage-restricted expression of functional Ncf1 restored arthritis resistance to the level of that of wild-type mice in a collagen-induced arthritis model but not in a T cell-independent anti-collagen antibody-induced arthritis model. T cell activation was downregulated and skewed toward Th2 in transgenic mice. In vitro, IL-2 production and T cell proliferation were suppressed by macrophage ROS, irrespective of T cell origin. IFN-gamma production, however, was independent of macrophage ROS but dependent on T cell origin. These effects were antigen dependent but not restricted to collagen type II. In conclusion, macrophage-derived ROS play a role in T cell selection, maturation, and differentiation, and also a suppressive role in T cell activation, and thereby mediate protection against autoimmune diseases like arthritis.
Gelderman
Kyra A
KA
Section of Medical Inflammation Research, Lund University, Lund, Sweden.
Hultqvist
Malin
M
Pizzolla
Angela
A
Zhao
Ming
M
Nandakumar
Kutty Selva
KS
Mattsson
Ragnar
R
Holmdahl
Rikard
R
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000276:immunology; D001168:Arthritis / Q000276:immunology*; D015551:Autoimmunity; D024043:Collagen Type II / Q000276:immunology; D005838:Genotype; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*
D000941:Antigens; D024043:Collagen Type II; D007376:Interleukin-2; D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1