Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species
Kyra A. Gelderman, Malin Hultqvist, Angela Pizzolla, Ming Zhao, Kutty Selva Nandakumar, Ragnar Mattsson, Rikard Holmdahl
Kyra A. Gelderman, Malin Hultqvist, Angela Pizzolla, Ming Zhao, Kutty Selva Nandakumar, Ragnar Mattsson, Rikard Holmdahl
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Research Article Autoimmunity

Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species

Abstract

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-γ 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.

Authors

Kyra A. Gelderman, Malin Hultqvist, Angela Pizzolla, Ming Zhao, Kutty Selva Nandakumar, Ragnar Mattsson, Rikard Holmdahl

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Figure 3

ROS production by macrophages decreases arthritis severity.

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ROS production by macrophages decreases arthritis severity. (A) Mice exp...
(A) Mice expressing functional Ncf1 on macrophages only (Ncf1*/*MN+: filled squares; n = 23) developed significantly less severe CIA as compared with Ncf1*/*MN– (open circles; n = 15) mice. After boost at day 35, a similar difference was also observed between Ncf1 heterozygous (+/*) mice with (n = 34) or without (n = 29) the transgene. No differences were observed in Ncf1 wild-type (+/+; n = 21 and 27) mice. All groups were included in each experiment. Mean ± SEM are shown of all mice, run in 2 different experiments with exactly the same setup, with the indicated total number of mice per group. #P < 0.05; †P < 0.005; ‡P < 0.0005. (B) Anti-CII IgG levels were determined at 10, 42, and 89 days after immunization and were significantly lower in transgene-positive (MN+) Ncf1*/* mice as compared with transgene-negative (MN–) Ncf1*/* mice. Sera from the CIA experiments as shown in A were used, with similar numbers of mice as indicated there. Means ± SEM are shown.