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

J Clin Invest. 2007 Oct;117(10):3020-8. doi: 10.1172/JCI31935.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigens / immunology
  • Arthritis / immunology*
  • Autoimmunity*
  • Collagen Type II / immunology
  • Genotype
  • Interferon-gamma / metabolism
  • Interleukin-2 / metabolism
  • Lymphocyte Activation
  • Macrophages / immunology*
  • Mice
  • Mice, Transgenic
  • Mutation
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Reactive Oxygen Species / metabolism*
  • Th1 Cells / immunology*


  • Antigens
  • Collagen Type II
  • Interleukin-2
  • Reactive Oxygen Species
  • Interferon-gamma
  • NADPH Oxidases
  • neutrophil cytosolic factor 1