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Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues
James C. Lo, … , Guido Franzoso, Yang-Xin Fu
James C. Lo, … , Guido Franzoso, Yang-Xin Fu
Published November 15, 2003
Citation Information: J Clin Invest. 2003;112(10):1495-1505. https://doi.org/10.1172/JCI19188.
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Article Immunology

Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues

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Abstract

CC chemokine ligand 21 (CCL21)/secondary lymphoid chemokine (SLC), a ligand for CC chemokine receptor 7 (CCR7), has been demonstrated to play a vital role in the homing and localization of immune cells to lymphoid tissues, but its role in nonlymphoid tissues largely remains undefined. Here, we provide evidence that CCL21 in lymphoid and nonlymphoid tissues is differentially regulated by lymphotoxin-dependent (LT-dependent) and -independent mechanisms, respectively. This differential regulation is due to the selective regulation of the CCL21-Ser/CCL21a but not the CCL21-Leu/CCL21b gene by the LT and noncanonical NF-κB pathways. This alternate pathway, not dependent on LT or lymphocytes, leading to constitutive expression of CCL21 in nonlymphoid tissues, is critical for the initial recruitment of T lymphocytes to peripheral effector sites. CCL21 expression is subsequently further enhanced in a LT-dependent fashion following airway challenge, potentially facilitating a positive feedback loop to attract additional CCR7+ effector cells. These findings establish an essential role for CCL21 in the recruitment of effector T cells to peripheral tissues and suggest that LT-dependent and -independent regulation of CCL21 plays a role in balancing the central and peripheral immune responses between lymphoid and nonlymphoid tissues.

Authors

James C. Lo, Robert K. Chin, Youjin Lee, Hyung-Sik Kang, Yang Wang, Joel V. Weinstock, Theresa Banks, Carl F. Ware, Guido Franzoso, Yang-Xin Fu

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Figure 5

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CCL21 and CCR7 on the T cell are required for homing to the lung. (a) Ph...
CCL21 and CCR7 on the T cell are required for homing to the lung. (a) Phenotypic characterization of T cells from lungs of SEA-challenged mice used in adoptive transfer experiments. Representative staining for CD4 and CD62L is shown. The numbers adjacent to the gates indicate the percentage of cells within the gates. A representative histogram is shown for CCR7 expression on gated CD4+ T cells using control human-Fc (red) and ELC-Fc (blue). (b) The CCR7 chemokine receptor on the T cell is required for homing to the lung. Lung cells from SEA-challenged mice were prelabeled with Thy1.2-PE and CFSE, treated with PBS or CCL19 to desensitize the CCR7 receptor, and adoptively transferred i.v. to naive LTα–/– mice. Recipient mice were killed 1 hour later, and the lungs were collected for analysis. Leukocytes were isolated from the lungs and subjected to flow cytometry analysis. Representative dot plots from control, CCR7 desensitized groups, and cells prior to transfer are shown. The numbers next to the gates indicate the percentage of cells within the gate. (c) CCL21 is required for T cell homing to the lung. Recipient mice were pretreated 1 hour prior to adoptive transfer with anti-CCL21 or control antibodies. Lung leukocytes were extracted 4 hours after adoptive transfer, and the T cells were enumerated. *P < 0.05 as calculated from Student’s t test. Data are pooled from at least four independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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