title: 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-kappaB 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: Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA.
authors: James C
authors: JC
authors: Lo
authors: Robert K
authors: RK
authors: Chin
authors: Youjin
authors: Y
authors: Lee
authors: Hyung-Sik
authors: HS
authors: Kang
authors: Yang
authors: Y
authors: Wang
authors: Joel V
authors: JV
authors: Weinstock
authors: Theresa
authors: T
authors: Banks
authors: Carl F
authors: CF
authors: Ware
authors: Guido
authors: G
authors: Franzoso
authors: Yang-Xin
authors: YX
authors: Fu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000276:immunology / Q000502:physiology; D008221:Lymphoid Tissue / Q000276:immunology* / Q000378:metabolism*; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: C515478:CCL21 protein, human; C515370:CCR7 protein, human; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018124:Receptors, Tumor Necrosis Factor