title: 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.
abstract: 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 Galpha(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 (T(GFP) cells). TCA-4 was constitutively presented on the luminal surface of HEVs, where it was required for LFA-1 activation on rolling T(GFP) cells. Desensitization of the TCA-4 receptor, CC chemokine receptor 7 (CCR7), blocked T(GFP) cell adherence in wild-type HEVs, whereas desensitization to stromal cell-derived factor (SDF)-1alpha (the ligand for CXC chemokine receptor 4 [CXCR4]) did not affect T(GFP) 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, T(GFP) 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 T(GFP) 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.
authors.affiliation: The Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: J V
authors.initials: JV
authors.lastname: Stein
authors.forename: A
authors.initials: A
authors.lastname: Rot
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.forename: M
authors.initials: M
authors.lastname: Narasimhaswamy
authors.forename: H
authors.initials: H
authors.lastname: Nakano
authors.forename: M D
authors.initials: MD
authors.lastname: Gunn
authors.forename: A
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: E J
authors.initials: EJ
authors.lastname: Quackenbush
authors.forename: M E
authors.initials: ME
authors.lastname: Dorf
authors.forename: U H
authors.initials: UH
authors.lastname: von Andrian
mesh_terms: D000818:Animals; D002465:Cell Movement; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000502:physiology*; D019743:Chemokines, CXC / Q000502:physiology; D004729:Endothelium, Lymphatic / Q000166:cytology*; D008198:Lymph Nodes / Q000166:cytology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1