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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Figure 1

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Leukocyte accumulation in lungs of LT-deficient mice. (a) Increased numb...
Leukocyte accumulation in lungs of LT-deficient mice. (a) Increased numbers of CD4+, B220+, and DCs in lungs of LTα–/– mice. Data are mean ± SD of triplicate samples and represent at least three independent experiments. (b) CCR7 expression on naive and activated phenotype pulmonary CD4+ T cells. Representative dot plots and histograms of CCR7 chemokine expression using ELC-Fc (blue lines) compared to control human-Fc (red lines) on CD4+CD62Lhigh and CD4+CD62Llow cells. (c) Altered homing of CD4+ T cells to the lungs of LTβR–/– mice. The spleens and lungs of WT and LTβR–/– mice were analyzed for the presence of OTII cells 2 days after adoptive transfer i.p. of Thy1.1+ OTII cells. Data are mean ± SD of four or more mice per group. *P < 0.05 between WT lung and WT spleen, and WT lung and LTβR–/– lung as calculated by the Student’s t test. Max, maximum.