Toll-like receptor 4 is required for optimal development of Th2 immune responses: role of dendritic cells.
LPS potently induces dendritic cell maturation and the production of proinflammatory cytokines, such as IL-12, by activation of Toll-like receptor 4 (TLR4). Since IL-12 is important for the generation and maintenance of Th1 responses and may also inhibit Th2 cell generation from naive CD4 T cell precursors, it has been inferred that TLR4 signaling would have similar effects via the induction of IL-12 secretion. Surprisingly, we found that TLR4-defective mice subjected to sensitization and pulmonary challenge with a protein allergen had reductions in airway inflammation with eosinophils, allergen-specific IgE levels, and Th2 cytokine production, compared with wild-type mice. These reduced responses were attributable, at least in part, to decreased dendritic cell function: Dendritic cells from TLR4-defective mice expressed lower levels of CD86, a costimulatory molecule important for Th2 responses. They also induced less Th2 cytokine production by antigenically naive CD4 T cells in vitro and mediated diminished CD4 T cell Ag-specific pulmonary inflammation in vivo. These results indicate that TLR4 is required for optimal Th2 responses to Ags from nonpathogenic sources and suggest a role for TLR4 ligands, such as LPS derived from commensal bacteria or endogenously derived ligands, in maturation of the innate immune system before pathogen exposure.
Dabbagh
Karim
K
Department of Pediatrics and the Immunology Program, Stanford University School of Medicine, Stanford, CA 94304, USA.
Dahl
Martin E
ME
Stepick-Biek
Pamela
P
Lewis
David B
DB
D000485:Allergens / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001249:Asthma / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D029721:Drosophila Proteins; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007073:Immunoglobulin E / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D009154:Mutation; D010047:Ovalbumin / Q000276:immunology; D011657:Pulmonary Eosinophilia / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D000485:Allergens; D015703:Antigens, CD; D016207:Cytokines; D029721:Drosophila Proteins; D000949:Histocompatibility Antigens Class II; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D007073:Immunoglobulin E; D010047:Ovalbumin