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Tregs can directly suppress macrophage TLR responses
Author(s) -
O’Leary Fionnuala,
Tajima Goro,
McKenna Ann,
MacConmara Malcolm,
Delisle Adam,
Mannick John,
Lederer James
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.672.50
Subject(s) - tlr4 , tlr2 , immunology , macrophage , il 2 receptor , toll like receptor , inflammation , cytokine , innate immune system , chemistry , biology , in vitro , immune system , t cell , biochemistry
Mice lacking CD4 T cells develop a more pro‐inflammatory phenotype when injured. We subsequently showed that CD4+CD25+ regulatory T cells (Tregs) were required to control this injury‐induced change in innate immunity. We now demonstrate that injured Treg‐deficient mice are more susceptible to LPS‐induced shock suggesting that Tregs play an active role in controlling Toll‐like receptor 4 (TLR4) reactivity. Since macrophages are the primary cells responsible for enhanced LPS reactivity after injury, we wished to test whether Tregs might directly control macrophage responses to innate stimuli. To accomplish this, we first developed a macrophage/Treg suppression assay. Macrophages were purified from the spleens and CD4+CD25+ T cells (Tregs) were purified from the lymph nodes of C57BL/6J mice. Cells were then mixed at various Treg:macrophage ratios and stimulated with pure LPS (a TLR4 agonist) or Pam3Cys‐Ser‐(Lys)4 (a TLR2 agonist) and anti‐CD3 antibody. Supernatants were then tested for TNF□, IL‐6, and IL‐10 levels. In some experiments, anti‐IL‐10 or anti‐TGFβ antibodies were tested as blocking reagents. Tregs from burn‐injured versus sham mice were also compared for Treg‐mediated suppression of macrophages. Our results indicate that Tregs can directly suppress TLR4‐ and TLR2‐induced inflammatory cytokine production by macrophages. Moreover, we find that both IL‐10 and TGFβ act synergistically to mediate the suppression of TLR4 and TLR2 responses by macrophages. Finally, we demonstrate that Tregs prepared from injured mice are more potent than sham Tregs at suppressing macrophage TLR2 and TLR4 responses. Taken together, our findings show that Tregs can actively suppress macrophage TLR responses through IL‐10‐and TGFβ‐dependent mechanisms and provide new insight into how Tregs control innate immune responses to injury and inflammation.