Impaired mucosal immunity in L-selectin-deficient mice orally immunized with a Salmonella vaccine vector.
Lymphocyte trafficking in the gastrointestinal tract is primarily mediated by interactions with the mucosal addressin cell adhesion molecule 1 and its lymphocyte ligand, alpha(4)beta(7), and partly by L-selectin (L-Sel) interactions with peripheral node addressin coexpressed on some mucosal addressin cell adhesion molecule 1. We inquired whether intestinal responses in mice lacking L-Sel would be enhanced. L-Sel-deficient (L-Sel(-/-)) mice were orally immunized with either Salmonella vaccine vector or Salmonella vector-expressing colonization factor Ag I (CFA/I) from enterotoxigenic Escherichia coli. In L-Sel(-/-) mice, mucosal IgA anti-CFA/I fimbrial responses were greatly reduced, and systemic IgG2a anti-CFA/I fimbrial responses were 26-fold greater compared with C57BL/6 (L-Sel(+/+)) mice. L-Sel(-/-) Peyer's patch (PP) CD4(+) Th cells revealed IFN-gamma-dominated responses and an unprecedented absence of IL-4, whereas the expected mixed Th cell phenotype developed in L-Sel(+/+) mice. PP CD4(+) Th cell anti-Salmonella responses were nearly nonexistent in L-Sel(-/-) mice immunized with either Salmonella vaccine. Splenic CD4(+) Th cell anti-Salmonella responses were reduced but did show cytokine production in Ag restimulation assays. Increased colonization of PP and spleen was noted only with the Salmonella vector in L-Sel(-/-) mice, resulting in increased splenomegaly, suggesting that the Salmonella-CFA/I vaccine was not as infectious or that the presence of the fimbriae improved clearance, possibly because of reduced neutrophil recruitment. However, sufficient anti-Salmonella immunity was induced, because Salmonella vector-immunized L-Sel(-/-) mice showed complete protection against wild-type Salmonella challenge, unlike L-Sel(+/+) mice. This evidence shows that L-Sel is important for development of mucosal immunity, and absence of L-Sel is protective against salmonellosis.
Pascual
D W
DW
Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, USA.
White
M D
MD
Larson
T
T
Walters
N
N
D000284:Administration, Oral; D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D036781:Fimbriae Proteins; D010861:Fimbriae, Bacterial / Q000276:immunology; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000276:immunology*; D018928:Immunity, Mucosal / Q000235:genetics; D007070:Immunoglobulin A / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology; D019041:L-Selectin / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics; D010581:Peyer's Patches / Q000276:immunology / Q000382:microbiology; D012481:Salmonella Infections, Animal / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D022562:Salmonella Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D012486:Salmonella typhimurium / Q000235:genetics* / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000382:microbiology; D013163:Splenomegaly / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018984:Epitopes, T-Lymphocyte; D007070:Immunoglobulin A; D022562:Salmonella Vaccines; D014614:Vaccines, Synthetic; C022924:colonization factor antigens; D019041:L-Selectin; D036781:Fimbriae Proteins