Abstract
After an inflammatory stimulus, lymphocyte migration into draining lymph nodes increases dramatically to facilitate the encounter of naive T cells with Ag-loaded dendritic cells. In this study, we show that CD73 (ecto-5'-nucleotidase) plays an important role in regulating this process. CD73 produces adenosine from AMP and is expressed on high endothelial venules (HEV) and subsets of lymphocytes. Cd73(-/-) mice have normal sized lymphoid organs in the steady state, but approximately 1.5-fold larger draining lymph nodes and 2.5-fold increased rates of L-selectin-dependent lymphocyte migration from the blood through HEV compared with wild-type mice 24 h after LPS administration. Migration rates of cd73(+/+) and cd73(-/-) lymphocytes into lymph nodes of wild-type mice are equal, suggesting that it is CD73 on HEV that regulates lymphocyte migration into draining lymph nodes. The A(2B) receptor is a likely target of CD73-generated adenosine, because it is the only adenosine receptor expressed on the HEV-like cell line KOP2.16 and it is up-regulated by TNF-alpha. Furthermore, increased lymphocyte migration into draining lymph nodes of cd73(-/-) mice is largely normalized by pretreatment with the selective A(2B) receptor agonist BAY 60-6583. Adenosine receptor signaling to restrict lymphocyte migration across HEV may be an important mechanism to control the magnitude of an inflammatory response.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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5'-Nucleotidase / genetics
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5'-Nucleotidase / immunology*
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5'-Nucleotidase / metabolism
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Adenosine / genetics
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Adenosine / immunology*
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Adenosine / metabolism
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Adenosine A2 Receptor Agonists
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Adenosine Monophosphate / genetics
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Adenosine Monophosphate / immunology
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Adenosine Monophosphate / metabolism
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Aminopyridines / pharmacology
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Animals
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Cell Movement / drug effects
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Cell Movement / genetics
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Cell Movement / immunology*
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Dendritic Cells / enzymology
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Dendritic Cells / immunology
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Endothelium, Vascular / enzymology
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Endothelium, Vascular / immunology*
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Inflammation / enzymology
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Inflammation / genetics
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Inflammation / immunology
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L-Selectin / immunology
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L-Selectin / metabolism
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Lipopolysaccharides / pharmacology
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Lymph Nodes / immunology*
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Mice
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Mice, Knockout
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Receptor, Adenosine A2B / immunology
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Receptor, Adenosine A2B / metabolism
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
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Tumor Necrosis Factor-alpha / metabolism
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Up-Regulation / drug effects
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Up-Regulation / genetics
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Up-Regulation / immunology
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Venules / enzymology
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Venules / immunology
Substances
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Adenosine A2 Receptor Agonists
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Aminopyridines
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BAY 60-6583
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Lipopolysaccharides
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Receptor, Adenosine A2B
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Tumor Necrosis Factor-alpha
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L-Selectin
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Adenosine Monophosphate
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5'-Nucleotidase
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Adenosine