title: TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice.
abstract: TLRs sense various microbial products. Their function has been best characterized in DCs and macrophages, where they act as important mediators of innate immunity. TLR4 is also expressed on CD4+ T cells, but its physiological function on these cells remains unknown. Here, we have shown that TLR4 triggering on CD4+ T cells affects their phenotype and their ability to provoke intestinal inflammation. In a model of spontaneous colitis, Il10-/-Tlr4-/- mice displayed accelerated development of disease, with signs of overt colitis as early as 8 weeks of age, when compared with Il10-/- and Il10-/-Tlr9-/- mice, which did not develop colitis by 8 months. Similar results were obtained in a second model of colitis in which transfer of naive Il10-/-Tlr4-/- CD4+ T cells into Rag1-/- recipients sufficient for both IL-10 and TLR4 induced more aggressive colitis than the transfer of naive Il10-/- CD4+ T cells. Mechanistically, LPS stimulation of TLR4-bearing CD4+ T cells inhibited ERK1/2 activation upon subsequent TCR stimulation via the induction of MAPK phosphatase 3 (MKP-3). Our data therefore reveal a tonic inhibitory role for TLR4 signaling on subsequent TCR-dependent CD4+ T cell responses.
authors.affiliation: Department of Medicine, UCSD, La Jolla, California, USA.
authors.forename: José M
authors.initials: JM
authors.lastname: González-Navajas
authors.forename: Sean
authors.initials: S
authors.lastname: Fine
authors.forename: Jason
authors.initials: J
authors.lastname: Law
authors.forename: Sandip K
authors.initials: SK
authors.lastname: Datta
authors.forename: Kim P
authors.initials: KP
authors.lastname: Nguyen
authors.forename: Mandy
authors.initials: M
authors.lastname: Yu
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.forename: Kyoko
authors.initials: K
authors.lastname: Katakura
authors.forename: Lars
authors.initials: L
authors.lastname: Eckman
authors.forename: Jongdae
authors.initials: J
authors.lastname: Lee
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003092:Colitis / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D018398:Homeodomain Proteins / Q000235:genetics; D016753:Interleukin-10 / Q000172:deficiency / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000172:deficiency / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000276:immunology* / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; D008070:Lipopolysaccharides; D016693:Receptors, Antigen, T-Cell, alpha-beta; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C064658:RAG-1 protein; D016753:Interleukin-10