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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.

Stein JV, Rot A, Luo Y, Narasimhaswamy M, Nakano H, Gunn MD, Matsuzawa A, Quackenbush EJ, Dorf ME, von Andrian UH - J. Exp. Med. (2000)

Bottom Line: 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.Accordingly, T(GFP) cells rolled but did not arrest in plt/plt HEVs.We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs.

View Article: PubMed Central - PubMed

Affiliation: The Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

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TCA-4 is presented on the luminal surface of wild-type, but not plt/plt, venules in PLNs. Fluorescent microvessels were recorded in anesthetized wild-type and plt/plt mice after intravenous injection of 75 μg anti–mouse TCA-4 mAb FITC-4B1. (A) PLN microvessels in a wild-type mouse. Note that fluorescent anti–TCA-4 delineates the HEV, but not an adjacent arteriole (ART). (B) Skin venules (VEN) or arterioles (ART) in the same wild-type mouse did not stain with anti–TCA-4. (C) FITC-4B1 did not accumulate in PLN venules of plt/plt mice. The extravascular bright spots were already present before mAb injection. These spots are most likely autofluorescent cells in the superficial cortex that are occasionally encountered in wild-type as well as plt/plt PLNs. Similar results were obtained in two other wild-type and plt/plt preparations. Bar, 100 μm. Digitized QuickTime™ videos showing characteristic scenes from intravital TCA-4 staining in wild-type and plt/plt mice (corresponding to A and C, respectively) are available at http://www.jem.org/cgi/content/full/191/1/61/F2/DC1.
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Figure 2: TCA-4 is presented on the luminal surface of wild-type, but not plt/plt, venules in PLNs. Fluorescent microvessels were recorded in anesthetized wild-type and plt/plt mice after intravenous injection of 75 μg anti–mouse TCA-4 mAb FITC-4B1. (A) PLN microvessels in a wild-type mouse. Note that fluorescent anti–TCA-4 delineates the HEV, but not an adjacent arteriole (ART). (B) Skin venules (VEN) or arterioles (ART) in the same wild-type mouse did not stain with anti–TCA-4. (C) FITC-4B1 did not accumulate in PLN venules of plt/plt mice. The extravascular bright spots were already present before mAb injection. These spots are most likely autofluorescent cells in the superficial cortex that are occasionally encountered in wild-type as well as plt/plt PLNs. Similar results were obtained in two other wild-type and plt/plt preparations. Bar, 100 μm. Digitized QuickTime™ videos showing characteristic scenes from intravital TCA-4 staining in wild-type and plt/plt mice (corresponding to A and C, respectively) are available at http://www.jem.org/cgi/content/full/191/1/61/F2/DC1.

Mentions: Digitized QuickTime™ videos showing characteristic scenes from intravital microscopy experiments of TGFP cell behavior and TCA-4 staining in wild-type and plt/plt mice are available at http://www.jem.org/cgi/content/full/191/1/61/DC1 (see legends to Fig. 2, Fig. 4, Fig. 6, and Fig. 7).


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.

Stein JV, Rot A, Luo Y, Narasimhaswamy M, Nakano H, Gunn MD, Matsuzawa A, Quackenbush EJ, Dorf ME, von Andrian UH - J. Exp. Med. (2000)

TCA-4 is presented on the luminal surface of wild-type, but not plt/plt, venules in PLNs. Fluorescent microvessels were recorded in anesthetized wild-type and plt/plt mice after intravenous injection of 75 μg anti–mouse TCA-4 mAb FITC-4B1. (A) PLN microvessels in a wild-type mouse. Note that fluorescent anti–TCA-4 delineates the HEV, but not an adjacent arteriole (ART). (B) Skin venules (VEN) or arterioles (ART) in the same wild-type mouse did not stain with anti–TCA-4. (C) FITC-4B1 did not accumulate in PLN venules of plt/plt mice. The extravascular bright spots were already present before mAb injection. These spots are most likely autofluorescent cells in the superficial cortex that are occasionally encountered in wild-type as well as plt/plt PLNs. Similar results were obtained in two other wild-type and plt/plt preparations. Bar, 100 μm. Digitized QuickTime™ videos showing characteristic scenes from intravital TCA-4 staining in wild-type and plt/plt mice (corresponding to A and C, respectively) are available at http://www.jem.org/cgi/content/full/191/1/61/F2/DC1.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195804&req=5

Figure 2: TCA-4 is presented on the luminal surface of wild-type, but not plt/plt, venules in PLNs. Fluorescent microvessels were recorded in anesthetized wild-type and plt/plt mice after intravenous injection of 75 μg anti–mouse TCA-4 mAb FITC-4B1. (A) PLN microvessels in a wild-type mouse. Note that fluorescent anti–TCA-4 delineates the HEV, but not an adjacent arteriole (ART). (B) Skin venules (VEN) or arterioles (ART) in the same wild-type mouse did not stain with anti–TCA-4. (C) FITC-4B1 did not accumulate in PLN venules of plt/plt mice. The extravascular bright spots were already present before mAb injection. These spots are most likely autofluorescent cells in the superficial cortex that are occasionally encountered in wild-type as well as plt/plt PLNs. Similar results were obtained in two other wild-type and plt/plt preparations. Bar, 100 μm. Digitized QuickTime™ videos showing characteristic scenes from intravital TCA-4 staining in wild-type and plt/plt mice (corresponding to A and C, respectively) are available at http://www.jem.org/cgi/content/full/191/1/61/F2/DC1.
Mentions: Digitized QuickTime™ videos showing characteristic scenes from intravital microscopy experiments of TGFP cell behavior and TCA-4 staining in wild-type and plt/plt mice are available at http://www.jem.org/cgi/content/full/191/1/61/DC1 (see legends to Fig. 2, Fig. 4, Fig. 6, and Fig. 7).

Bottom Line: 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.Accordingly, T(GFP) cells rolled but did not arrest in plt/plt HEVs.We conclude that TCA-4 is both required and sufficient for LFA-1 activation on rolling T cells in PLN HEVs.

View Article: PubMed Central - PubMed

Affiliation: The Center for Blood Research, Harvard Medical School, Boston, Massachusetts 02115, USA.

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.

Show MeSH
Related in: MedlinePlus