Lymphotoxin plays a crucial role in the development and function of nasal-associated lymphoid tissue through regulation of chemokines and peripheral node addressin.
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)-alpha, LT-beta, 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-beta(-/-) and LT-alpha(-/-) NALTs had fewer cells than those of wild-type mice, reduced (LT-beta(-/-)) or absent (LT-alpha(-/-)) lymphoid chemokines, and no T- and B-cell compartmentalization. LT-beta(-/-) HEVs expressed only abluminal PNAd and no HEC-6ST or GlyCAM-1. LT-alpha(-/-) HEVs had no PNAd, HEC-6ST, or GlyCAM-1. Because intranasal immunization gives rise to vaginal IgA, immunization of LT-beta(-/-) 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-alpha(-/-) and LT-beta(-/-) NALTs, and undetectable vaginal IgA. In contrast, splenic cytokines and serum IgG titers, although reduced, were detectable. These data indicate that LT-alpha(3) and LT-alpha(1)beta(2) cooperatively contribute to NALT development and function through regulation of lymphoid chemokines and adhesion molecules; they are the first to implicate LT-alpha(1)beta(2) in GlyCAM-1 regulation in NALT HEV development.
Ying
Xiaoyan
X
Yale University School of Medicine, Department of Epidemiology and Public Health, 60 College St., P.O. Box 208034, New Haven, CT 06520-8034, USA.
Chan
Kee
K
Shenoy
Priti
P
Hill
Myriam
M
Ruddle
Nancy H
NH
D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology; D018925:Chemokines / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D008221:Lymphoid Tissue / Q000276:immunology*; D008233:Lymphotoxin-alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000502:physiology*; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D014699:Venules / Q000276:immunology / Q000502:physiology
D000954:Antigens, Surface; D018925:Chemokines; C069886:L-selectin counter-receptors; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins