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(American Journal of Pathology. 2005;166:135-146.)
© 2005 American Society for Investigative Pathology

Lymphotoxin Plays a Crucial Role in the Development and Function of Nasal-Associated Lymphoid Tissue through Regulation of Chemokines and Peripheral Node Addressin

Xiaoyan Ying^*, Kee Chan^*, Priti Shenoy^*, Myriam Hill^* and Nancy H. Ruddle^*

From the Department of Epidemiology and Public Health^* and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut

The mechanism of nasal-associated lymphoid tissue (NALT) development is incompletely understood with regard to the roles of cytokines, chemokines, and vascular addressins. Development of the wild-type NALT continued in the immediate postnatal period with gradual increases in cellularity, compartmentalization into T- and B-cell zones, and expression of lymphotoxin (LT)-, LT-ß, and lymphoid chemokines (CCL21, CCL19, CXCL13). High endothelial venules (HEVs) developed that expressed GlyCAM-1, HEC-6ST [an enzyme crucial for expression of luminal peripheral node addressin (PNAd)], and PNAd itself. LT-ß^–/– and LT-^–/– NALTs had fewer cells than those of wild-type mice, reduced (LT-ß^–/–) or absent (LT-^–/–) lymphoid chemokines, and no T- and B-cell compartmentalization. LT-ß^–/– HEVs expressed only abluminal PNAd and no HEC-6ST or GlyCAM-1. LT-^–/– HEVs had no PNAd, HEC-6ST, or GlyCAM-1. Because intranasal immunization gives rise to vaginal IgA, immunization of LT-ß^–/– mice, which retain cervical lymph nodes, might generate such a response. Intranasal immunization with ovalbumin and cholera toxin revealed lower cytokine levels in the LT-^–/– and LT-ß^–/– NALTs, and undetectable vaginal IgA. In contrast, splenic cytokines and serum IgG titers, although reduced, were detectable. These data indicate that LT-₃ and LT-₁ß₂ cooperatively contribute to NALT development and function through regulation of lymphoid chemokines and adhesion molecules; they are the first to implicate LT-₁ß₂ in GlyCAM-1 regulation in NALT HEV development.

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