title: Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity.
abstract: Allergic contact hypersensitivity (CHS) is a T cell-mediated inflammatory skin disease. Interleukin (IL)-12 is considered to be important in the generation of the allergen-specific T cell response. Loss of IL-12 function in IL-12Rbeta2-deficient mice, however, did not ameliorate the allergic immune response, suggesting alternate IL-12-independent pathways in the induction of CHS. Because exposure to contact allergens always takes place in the presence of microbial skin flora, we investigated the potential role of Toll-like receptors (TLRs) in the induction of CHS. Using mice deficient in TLR4, the receptor for bacterial lipopolysaccharide (LPS), IL-12 receptor (R) beta2, or both, we show that the concomitant absence of TLR4 and IL-12Rbeta2, but not the absence of TLR4 or IL-12Rbeta2 alone, prevented DC-mediated sensitization, generation of effector T cells, and the subsequent CHS response to 2,4,6-trinitro-1-chlorobenzene (TNCB), oxazolone, and fluorescein isothiocyanate. Introduction of the TLR4 transgene into the TLR4/IL-12Rbeta2 mutant restored the CHS inducibility, showing a requirement for TLR4 in IL-12-independent CHS induction. Furthermore, the concomitant absence of TLR2 and TLR4 prevented the induction of CHS to TNCB in IL-12-competent mice. Finally, CHS was inducible in germ-free wild-type and IL-12Rbeta2-deficient mice, but not in germ-free TLR4/IL-12Rbeta2 double deficient mice, suggesting that the necessary TLR activation may proceed via endogenous ligands.
authors: Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, D-79104 Freiburg, Germany. stefan.martin@uniklinik-freiburg.de
authors: Stefan F
authors: SF
authors: Martin
authors: Jan C
authors: JC
authors: Dudda
authors: Eva
authors: E
authors: Bachtanian
authors: Annalisa
authors: A
authors: Lembo
authors: Stefanie
authors: S
authors: Liller
authors: Christoph
authors: C
authors: Dürr
authors: Markus M
authors: MM
authors: Heimesaat
authors: Stefan
authors: S
authors: Bereswill
authors: György
authors: G
authors: Fejer
authors: Ralitsa
authors: R
authors: Vassileva
authors: Thilo
authors: T
authors: Jakob
authors: Nikolaus
authors: N
authors: Freudenberg
authors: Christian C
authors: CC
authors: Termeer
authors: Caroline
authors: C
authors: Johner
authors: Chris
authors: C
authors: Galanos
authors: Marina A
authors: MA
authors: Freudenberg
mesh_terms: D000485:Allergens / Q000737:chemistry; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D003877:Dermatitis, Contact / Q000276:immunology*; D005260:Female; D018664:Interleukin-12 / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D000485:Allergens; D016207:Cytokines; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018664:Interleukin-12