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* Immunobiology and Cancer Program and
Cardiovascular Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104;
Department of Periodontology, Division of Oral Biology and Disease Control, Osaka University Graduate School of Dentistry, Osaka, Japan;
Laboratory of Immunobiology, Hyogo University of Health Sciences, Kobe, Japan;
¶ Laboratory of Molecular and Cellular Recognition, Osaka University Graduate School of Medicine, Osaka, Japan;
|| Bayer HealthCare, Wuppertal, Germany; and
# Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, TX 77030
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 
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 A2B 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-
. Furthermore, increased lymphocyte migration into draining lymph nodes of cd73–/– mice is largely normalized by pretreatment with the selective A2B 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI18220 (to L.F.T.), P01 HL085607 (to R.P.M.), and AI43472 (to M.R.B.), and was part of the 21st Century Center of Excellence entitled "Origination of Frontier BioDentistry" at Osaka University Graduate School of Dentistry supported by the Ministry of Education, Culture, Sports, Science, and Technology. L.F.T. holds the Putnam City Schools Distinguished Chair in Cancer Research. R.P.M. holds the Eli Lilly Distinguished Chair in Biomedical Research.
2 Current address: Department of Molecular Genetics, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan 570-8506.
3 Address correspondence and reprint requests to Dr. Linda F. Thompson, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104. E-mail address: Linda-Thompson{at}omrf.org
4 Abbreviations used in this paper: HEV, high endothelial venule; Ado, adenosine; AR, Ado receptor; CMFDA, 5-chloromethylfluorescein diacetate; CMTMR, 5(and 6)-(((4-chloromethyl)benzoyl)amino)tetramethylrhodamine; DC, dendritic cell; PEG, polyethylene glycol; PNAd, peripheral lymph node addressin.
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