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

Gelderman, Kyra LU ; Hultqvist, Malin LU ; Pizzolla, Angela LU ; Zhao, Ming LU ; Kutty Selva, Nandakumar LU ; Mattsson, Ragnar LU and Holmdahl, Rikard LU (2007) In Journal of Clinical Investigation 117(10). p.3020-3028
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Investigation
volume
117
issue
10
pages
3020 - 3028
publisher
The Journal of Clinical Investigation
external identifiers
  • wos:000249894400032
  • scopus:34948814168
ISSN
0021-9738
DOI
10.1172/JCI31935
language
English
LU publication?
yes
id
4fb8cf75-c30f-4329-973d-66b89558ab86 (old id 655693)
date added to LUP
2007-12-10 14:39:26
date last changed
2017-11-19 04:05:23
@article{4fb8cf75-c30f-4329-973d-66b89558ab86,
  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-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.},
  author       = {Gelderman, Kyra and Hultqvist, Malin and Pizzolla, Angela and Zhao, Ming and Kutty Selva, Nandakumar and Mattsson, Ragnar and Holmdahl, Rikard},
  issn         = {0021-9738},
  language     = {eng},
  number       = {10},
  pages        = {3020--3028},
  publisher    = {The Journal of Clinical Investigation},
  series       = {Journal of Clinical Investigation},
  title        = {Macrophages suppress T cell responses and arthritis development in mice by producing reactive oxygen species},
  url          = {http://dx.doi.org/10.1172/JCI31935},
  volume       = {117},
  year         = {2007},
}