Background: Exposure of skin to UVB radiation (290-320 nm) modulates the immune system, with most studies showing a suppression of Th1-driven immune responses. Investigations into the effects of UVB exposure on allergic respiratory responses have been limited. This study investigated the systemic effects of UVB on Th2-associated immune responses using two different murine models of allergic respiratory inflammation. The mechanism of immune regulation was also examined. Methods and Results: Two murine models of asthma were used: the papain model and the ovalbumin (OVA) model using papain and OVA, respectively, as the allergens. In the papain model, C57BL/6, histamine receptor-1 knockout (H1RKO) and histamine receptor-2 knockout (H2RKO) mice were exposed to a single 4 kJ/m2 dose of UVB (twice a minimal oedemal dose) on shaved dorsal skin three days prior to intranasal sensitisation with papain, a cysteine protease homologue of the house dust mite (Dermatophagoides pteronyssinus) allergen Der p 1. Sensitisation and boost each consisted of five daily intranasal doses of 1 µg papain whilst the challenge consisted of three daily intranasal doses of 100 µg papain. Asthmatic symptoms were assessed 24 h after the final challenge dose. H1RKO mice demonstrated enhanced papain-specific inflammatory responses in the lung-draining lymph nodes (LDLNs) whilst the responses of H2RKO mice closely mimicked those of C57BL/6 mice. UVB irradiation three days before sensitisation reduced in vitro papain-specific proliferation of LDLN cells from C57BL/6 and H1RKO mice but not H2RKO mice 24 h after challenge. The regulatory effect of UVB was transferred by adoptive transfer of 5 x 106 unfractionated LDLN cells from UVB-irradiated, papain-sensitised and -challenged C57BL/6 and H1RKO donor mice into naïve recipients of the corresponding strain that were ii subsequently sensitised and challenged with papain. Additionally, UVB exposure suppressed papain-induced IL-5 and IL-10 production in vitro by LDLN cells from H1RKO mice but not from C57BL/6 mice or H2RKO mice. The results of this study demonstrate systemic immunomodulation of responses to intranasally delivered antigen by UVB irradiation and the induction of regulatory cells in the LDLN following UVB exposure. Furthermore, these results implicate a role for the H2R in UVB-induced suppression of antigen-specific responses in the draining lymph nodes.