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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Airway inflammation induces the CCL21-Ser gene in an LT-dependent fashio...
Airway inflammation induces the CCL21-Ser gene in an LT-dependent fashion. (a) LTβR signaling specifically induces CCL21-Ser. WT mice were injected i.p. with control or agonistic LTβR antibodies. RNA from the spleens and lungs were analyzed by real-time PCR for CCL21-Ser and CCL21-Leu. Each point reflects the fold induction in CCL21. (b) Spleen and lung cells respond to LTβR signals. Representative histograms of stromal cells from the spleen or lung stimulated with species control (black) or agonistic anti-LTβR (gray) antibody and stained with VCAM-1 antibody for analysis by flow cytometry is shown. (c) Airway inflammation induction of CCL21 in the lung is LT-dependent. WT or LTα–/– mice were challenged with SEA and control or anti-LTβ antibodies were administered i.p. during the challenge phase only. Mice were killed 3 to 4 days after challenge and pulmonary CCL21 quantified as previously described (see Figure 3a). Student’s t tests were performed between naive and challenged, control challenged and anti-LTβ–challenged, and WT and LTα–/– SEA-challenged groups and the resultant P values are shown. (d) Airway inflammation specifically induces the CCL21-Ser gene. Real-time PCR for the two CCL21 genes was performed on RNA extracted from lungs of naive and SEA-challenged WT and LTα–/– mice. PCR reactions were performed in duplex with a GAPDH internal control for normalization. Columns and bars represent the mean ± SD.