Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species
Kyra A. Gelderman, … , Ragnar Mattsson, Rikard Holmdahl
Kyra A. Gelderman, … , Ragnar Mattsson, Rikard Holmdahl
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):3020-3028. https://doi.org/10.1172/JCI31935.
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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.