The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/61/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 1, January 3, 2000 61-76

Original Article

The CC Chemokine Thymus-derived Chemotactic Agent 4 (TCA-4, Secondary Lymphoid Tissue Chemokine, 6Ckine, Exodus-2) Triggers Lymphocyte Function–associated Antigen 1–mediated Arrest of Rolling T Lymphocytes in Peripheral Lymph Node High Endothelial Venules

Jens V. Steina, Antal Rotd, Yi Luob, Manjunath Narasimhaswamya, Hideki Nakanoe, Michael D. Gunnf, Akio Matsuzawag, Elizabeth J. Quackenbusha,c, Martin E. Dorfb, and Ulrich H. von Andriana,b
a The Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115
b Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
c Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115
d Novartis Forschungsinstitut, A-1235 Vienna, Austria
e Department of Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan
f Division of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
g Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan

Correspondence to: Ulrich H. von Andrian, The Center for Blood Research and Department of Pathology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115. Tel:617-278-3130 Fax:617-278-3190 E-mail:uva{at}cbr.med.harvard.edu.

T cell homing to peripheral lymph nodes (PLNs) is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial tethering and rolling via L-selectin, firm adhesion of T cells requires rapid upregulation of lymphocyte function–associated antigen 1 (LFA-1) adhesiveness by a previously unknown pathway that activates a G{alpha}i-linked receptor. Here, we used intravital microscopy of murine PLNs to study the role of thymus-derived chemotactic agent (TCA)-4 (secondary lymphoid tissue chemokine, 6Ckine, Exodus-2) in homing of adoptively transferred T cells from T-GFP mice, a transgenic strain that expresses green fluorescent protein (GFP) selectively in naive T lymphocytes (TGFP cells). TCA-4 was constitutively presented on the luminal surface of HEVs, where it was required for LFA-1 activation on rolling TGFP cells. Desensitization of the TCA-4 receptor, CC chemokine receptor 7 (CCR7), blocked TGFP cell adherence in wild-type HEVs, whereas desensitization to stromal cell–derived factor (SDF)-1{alpha} (the ligand for CXC chemokine receptor 4 [CXCR4]) did not affect TGFP cell behavior. TCA-4 protein was not detected on the luminal surface of PLN HEVs in plt/plt mice, which have a congenital defect in T cell homing to PLNs. Accordingly, TGFP cells rolled but did not arrest in plt/plt HEVs. When TCA-4 was injected intracutaneously into plt/plt mice, the chemokine entered afferent lymph vessels and accumulated in draining PLNs. 2 h after intracutaneous injection, luminal presentation of TCA-4 was detectable in a subset of HEVs, and LFA-1–mediated TGFP cell adhesion was restored in these vessels. We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs. This study also highlights a hitherto undocumented role for chemokines contained in afferent lymph, which may modulate leukocyte recruitment in draining PLNs.

Key Words: homing, intravital microscopy, adhesion, T cell


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