title: Dual TCR expression biases lung inflammation in DO11.10 transgenic mice and promotes neutrophilia via microbiota-induced Th17 differentiation.
abstract: A commonly used mouse model of asthma is based on i.p. sensitization to OVA together with aluminum hydroxide (alum). In wild-type BALB/c mice, subsequent aerosol challenge using this protein generates an eosinophilic inflammation associated with Th2 cytokine expression. By constrast, in DO11.10 mice, which are transgenic for an OVA-specific TCR, the same treatment fails to induce eosinophilia, but instead promotes lung neutrophilia. In this study, we show that this neutrophilic infiltration results from increased IL-17A and IL-17F production, whereas the eosinophilic response could be restored upon blockade of IFN-γ, independently of the Th17 response. In addition, we identified a CD4(+) cell population specifically present in DO11.10 mice that mediates the same inflammatory response upon transfer into RAG2(-/-) mice. This population contained a significant proportion of cells expressing an additional endogenous TCR α-chain and was not present in RAG2(-/-) DO11.10 mice, suggesting dual antigenic specificities. This particular cell population expressed markers of memory cells, secreted high levels of IL-17A, and other cytokines after short-term restimulation in vitro, and triggered a neutrophilic response in vivo upon OVA aerosol challenge. The relative numbers of these dual TCR lymphocytes increased with the age of the animals, and IL-17 production was abolished if mice were treated with large-spectrum antibiotics, suggesting that their differentiation depends on foreign Ags provided by gut microflora. Taken together, our data indicate that dual TCR expression biases the OVA-specific response in DO11.10 mice by inhibiting eosinophilic responses via IFN-γ and promoting a neutrophilic inflammation via microbiota-induced Th17 differentiation.
authors.affiliation: Ludwig Institute for Cancer Research, Brussels Branch, B-1200 Brussels, Belgium.
authors.forename: Muriel M
authors.initials: MM
authors.lastname: Lemaire
authors.forename: Laure
authors.initials: L
authors.lastname: Dumoutier
authors.forename: Guy
authors.initials: G
authors.lastname: Warnier
authors.forename: Catherine
authors.initials: C
authors.lastname: Uyttenhove
authors.forename: Jacques
authors.initials: J
authors.lastname: Van Snick
authors.forename: Magali
authors.initials: M
authors.lastname: de Heusch
authors.forename: Monique
authors.initials: M
authors.lastname: Stevens
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Renauld
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology
chemical_list: D020381:Interleukin-17; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma; D010047:Ovalbumin