Keratinocytes play a pivotal role in the regulation of immune responses but the impact of antigen-presentation by these cells is still poorly understood, particularly in a situation where the antigen will be presented only in adult life. Here, we generated a transgenic mouse model in which keratinocytes exclusively present a myelin basic protein (MBP) peptide covalently linked to the MHC class II β-chain, solely under inflammatory conditions. In these mice, inflammation caused by epicutaneous contact sensitizer treatment resulted in keratinocyte-mediated expansion of MBP-specific CD4(+) T cells in the skin. Moreover, repeated contact sensitizer application preceding a systemic MBP immunization reduced the reactivity of the respective CD4(+) T cells and lowered the symptoms of the resulting experimental autoimmune encephalomyelitis. This down-regulation was CD4(+) T cell mediated and dependent on the presence of the immune modulator Dickkopf-3. Thus, presentation of a neo self-antigen by keratinocytes in the inflamed, adult skin can modulate CD4(+) T cell auto-aggression at a distal organ.In parallel to the DPCP skin treatments, 0.5 mg of the anti-Dkk3 4.22 mAb (Papatriantafyllou et al., 2012) in 200 μl PBS was applied i.p., 3 times, each one week apart.Journal of Investigative Dermatology accepted article preview online, 02 April 2015. doi:10.1038/jid.2015.130.