Toll-like receptor and IL-12 signaling control susceptibility to contact hypersensitivity.
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.
Martin
Stefan F
SF
Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, D-79104 Freiburg, Germany. stefan.martin@uniklinik-freiburg.de
Dudda
Jan C
JC
Bachtanian
Eva
E
Lembo
Annalisa
A
Liller
Stefanie
S
Dürr
Christoph
C
Heimesaat
Markus M
MM
Bereswill
Stefan
S
Fejer
György
G
Vassileva
Ralitsa
R
Jakob
Thilo
T
Freudenberg
Nikolaus
N
Termeer
Christian C
CC
Johner
Caroline
C
Galanos
Chris
C
Freudenberg
Marina A
MA
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*
D000485:Allergens; D016207:Cytokines; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D018664:Interleukin-12