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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Model for the dual roles of CCL21 in central and peripheral immune respo...
Model for the dual roles of CCL21 in central and peripheral immune responses. (I) Pathogen breaches and infects the lung/nonlymphoid tissue where antigen is picked up by DCs, which along with naive T cells migrate to the draining lymph node/lymphoid tissue through CCL21-Ser/CCR7 interactions. (II) DCs prime antigen-specific T cells leading to their activation, proliferation, and differentiation. (III) The initial wave of primed T cells enters the circulation and migrates to the lung directed by the constitutively expressed CCL21, which is independent of lymphocytes and LT. (IV) LT expressed by activated T cells in the lung stimulates the LTβR on stromal cells, further inducing CCL21 expression via CCL21-Ser to attract additional T cells, resulting in a positive feedback loop. Additionally, the induced CCL21 may be localized to infected microregions within the lung to enhance targeting of effector cells to those infected areas. LT may also be derived from other inflammatory cells.