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* Program in Molecular Pathogenesis, Kimmel Center for Biology and Medicine, Skirball Institute, New York University School of Medicine, New York, NY 10016;
Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27708;
Laboratory of Trauma, Sepsis and Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, OH 45267;
Department of Internal Medicine, Section of Nephrology, University of Nebraska Medical Center, Omaha, NE 68198;
¶ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095;
|| Division of Nephrology, Duke University, Durham Veterans Affairs Medical Centers, Durham, NC 27705;
# Divisions of Clinical Pharmacology and Rheumatology, Department of Medicine, New York University School of Medicine, New York, NY 10016;
** Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029;
Departments of Biology and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115; and
* Department of Radiation Oncology, Duke University Medical Center, Duke University, Durham, NC 27710
Although the requirements for T lymphocyte homing to lymph nodes (LNs) are well studied, much less is known about the requirements for T lymphocyte locomotion within LNs. Imaging of murine T lymphocyte migration in explanted LNs using two-photon laser-scanning fluorescence microscopy provides an opportunity to systematically study these requirements. We have developed a closed system for imaging an intact LN with controlled temperature, oxygenation, and perfusion rate. Naive T lymphocyte locomotion in the deep paracortex of the LN required a perfusion rate of >13 µm/s and a partial pressure of O2 (pO2) of >7.4%. Naive T lymphocyte locomotion in the subcapsular region was 38% slower and had higher turning angles and arrest coefficients than naive T lymphocytes in the deep paracortex. T lymphocyte activation decreased the requirement for pO2, but also decreased the speed of locomotion in the deep paracortex. Although CCR7–/– naive T cells displayed a small reduction in locomotion, systemic treatment with pertussis toxin reduced naive T lymphocyte speed by 59%, indicating a contribution of G
i-mediated signaling, but involvement of other G protein-coupled receptors besides CCR7. Receptor knockouts or pharmacological inhibition in the adenosine, PG/lipoxygenase, lysophosphatidylcholine, and sphingosine-1-phosphate pathways did not individually alter naive T cell migration. These data implicate pO2, tissue architecture, and G-protein coupled receptor signaling in regulation of naive T lymphocyte migration in explanted LNs.
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 AI55037 (to M.L.D.) and DK38108 (to T.J.P. and P.N.R.) and the Irene Diamond Foundation (to M.L.D.).
2 Address correspondence and reprint requests to Dr. Michael L. Dustin, Program in Molecular Pathogenesis, Skirball Institute, New York University Medical Center, 540 First Avenue, New York, NY 10016. E-mail address: dustin{at}saturn.med.nyu.edu
3 Abbreviations used in this paper: DC, dendritic cell; LN, lymph node; pO2, partial pressure of O2; 3D, three dimensional; PTX, pertussis toxin; WT, wild type; GPCR, G protein-coupled receptor; TP, thromboxane-prostanoid receptor; ETYA, 5,8,11,14-eicosatetraynoic acid; 2D, two dimensional; A2AR, A2A adenosine receptor; S1P, shpingosine-1-phospate.
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