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

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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CCL21 is differentially regulated in the spleen and lung. (a) LT signals...
CCL21 is differentially regulated in the spleen and lung. (a) LT signals are essential for spleen but not lung CCL21. ELISA for CCL21 was performed on spleen and lung homogenates prepared from various LT-deficient mice. Each sample was normalized by tissue weight. (b) Differential requirements for NF-κB and lymphocytes in the expression of CCL21 in the spleen and lung. ELISA for splenic and lung CCL21 from various NF-κB–deficient and Rag–/– mice, calculated as in a. Each symbol represents data from a single mouse. (c, d) LT selectively regulates the expression of CCL21-Ser but not CCL21-Leu. Real-time PCR analysis was performed on the spleen and lung of WT and LTα–/– mice with conditions specific for CCL21-Ser (c) and CCL21-Leu (d). The columns and bars represent the mean ± SD.