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

DOI PDF 被引用文献11件
  • Jens V. Stein
    aThe Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115
  • Antal Rot
    dNovartis Forschungsinstitut, A-1235 Vienna, Austria
  • Yi Luo
    bDepartment of Pathology, Harvard Medical School, Boston, Massachusetts 02115
  • Manjunath Narasimhaswamy
    aThe Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115
  • Hideki Nakano
    eDepartment of Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan
  • Michael D. Gunn
    fDivision of Cardiology, Duke University Medical Center, Durham, North Carolina 27710
  • Akio Matsuzawa
    gInstitute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
  • Elizabeth J. Quackenbush
    aThe Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115
  • Martin E. Dorf
    bDepartment of Pathology, Harvard Medical School, Boston, Massachusetts 02115
  • Ulrich H. von Andrian
    aThe Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115

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<jats:p>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 Gαi-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)-1α (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.</jats:p>

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