Regulatory T cells in the skin suppress percutaneous sensitization by regulating dermal dendritic cell function

Regulatory T cells in the skin suppress percutaneous sensitization by regulating dermal dendritic cell function

Abstracts from the 41st Annual Meeting / Journal of Dermatological Science 86 (2017) e1–e95 P10-05[C09-4] Prolonged incubation period after initial H...

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Abstracts from the 41st Annual Meeting / Journal of Dermatological Science 86 (2017) e1–e95

P10-05[C09-4] Prolonged incubation period after initial HIV infection is mediated by CTL activation and Treg cell suppression induced by Langerhans cells Takamitsu Matsuzawa ∗ , Tatsuyoshi Kawamura, Youichi Ogawa, Shinji Shimada Dermatology, University of Yamanashi, Yamanashi, Japan Langerhans cells (LCs) are one of the initial target cells for HIV. However, little is known on the modulation of HIV-specific immune responses by HIV-infected LCs, such as the induction of HIV-specific CD8+ T cells and CD4+ regulatory T (Treg) cells, both of which play important roles in controlling HIV replication in infected individuals. To investigate the inducibility of HIV-specific CD8+ T cells by HIV-infected LCs, naive CD8+ T cells from HLAA0201 healthy donors (n = 3) were cocultured with HIVBaL -infected autologous monocyte-derived LCs (mLCs) or monocytederived DCs (mDCs) as a control. 7 days later, primed CD8+ T cells were restimulated by HIVBaL -infected autologous mLCs/mDCs for 7 days. The number of HIV gag tetramer+ CD8+ T cells induced by HIVinfected mLCs was significantly higher than that induced by mDCs. Moreover, IFN-␥ production of HIV gag tetramer+ CD8+ T cells induced by HIV-infected mLCs was significantly higher than that of tetramer- CD8+ T cells. Likewise, ex vivo HIVBaL -infected human epidermal LCs induced IFN-␥ producing HIV-specific CD8+ T cells (n = 2). Next, to investigate the inducibility of Treg cells by HIV-infected LCs, naive CD4+ T cells were cocultured with HIVBaL infected autologous mLCs or epidermal LCs for 6 days (n = 3 each). Treg cells have recently been classified into three subpopulations: FoxP3hi CD45RA− , FoxP3lo CD45RA+ , and FoxP3lo CD45RAcells. The number of FoxP3hi CD45RA− Treg cells induced by HIV-infected mLCs or epidermal LCs was significantly lower than that induced by uninfected mLCs or epidermal LCs. Taking these results together, HIV-infected LCs trigger beneficial anti-HIV immune responses in the initial HIV infection phase, thereby contributing to the prolonged incubation period from initial HIV infection to AIDS onset. http://dx.doi.org/10.1016/j.jdermsci.2017.02.189 P10-06[C09-5] Air pollution activates Aryl hydrocarbon receptor in murine epidermis, leading to Atopic dermatitis-like pathologies Takanori Hidaka 1,∗ , Eri H. Kobayashi 2 , Takafumi Suzuki 2 , Masayuki Yamamoto 2 1 The Department of Dermatology, University of Tohoku, Sendai, Japan 2 The Department of Medical Biochemistry, University of Tohoku, Sendai, Japan Recent epidemiologic studies revealed a correlation between rapid increase in the prevalence of atopic dermatitis (AD) and air pollution levels. Polycyclic aromatic hydrocarbons (PAHs) were identified as the component responsible for the air pollutantinduced inflammation. They exert biological effects by binding to a transcription factor, aryl hydrocarbon receptor (AhR). To investigate mechanisms underlying the air pollution-induced AD, we have established transgenic mouse lines that express constitutive-active form of AhR under keratin-14 promoter (AhRCA mice), which mimic the chronic exposure of air pollutants to the skin. In this study, we found that AhR-CA mice recapitulate various characteristics of human AD, including tiny tactile pain-induced scratch behavior (alloknesis), increased trans-

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epidermal water loss, infiltration of allergic cells into the dermis, and percutaneous sensitization to topically applied protein antigen. We also found hyper-innervation at epidermis, which may be the cause of alloknesis. Furthermore, to explorer the effect of chronic AhR activation by air pollutant, we applied 7,12dimethylbenz[a]anthracene (DMBA), a typical PAHs of air pollutant, on the skin of AhRflox/flox or AhRflox/flox ::K5-Cre mice. The skin of DMBA-applied AhRflox/flox mice revealed scaling, the infiltration of T cells and mast cells, elevated serum IgE level, scratching behavior, alloknesis and epidermal hyperinnervation but that of DMBAapplied AhRflox/flox ::K5-Cre mice didnot. These results suggest that epicutaneouslly exposed-air pollutants will penetrate through skin and activate AhR of epidermis, that is one of the possible mechanisms of air pollutant-induced AD. http://dx.doi.org/10.1016/j.jdermsci.2017.02.190 P10-07[C09-6] Regulatory T cells in the skin suppress percutaneous sensitization by regulating dermal dendritic cell function Sho Hanakawa, Akihiko Kitoh ∗ , Kenji Kabashima Department of Dermatology, Kyoto University Graduate School of Medicine, Japan CD4+Foxp3+ regulatory T cells (Tregs) play an important role in suppressing excessive immune responses. There are a substantial number of Tregs in the skin even in a steady state. However, it remains unclear whether and how cutaneous Tregs regulate immune responses to percutaneous antigen exposure. To address this issue, we established an experimental technique for selectively eliminating cutaneous Tregs and investigated their role in the regulation of percutaneous sensitization using contact hypersensitivity (CHS) model. Intradermal injection with low-dose diphtheria toxin (DT) into the ear skin of Foxp3-DTR mice, in which Foxp3+ Tregs specifically express DT receptor, reduced Tregs only in the treated skin. Foxp3DTR mice sensitized with 2,4-dinitrofluorobenzene (DNFB) through DT-treated skin showed significantly exacerbated CHS reaction elicited in the Treg sufficient contra lateral ear. Consistent with the exacerbated CHS, sensitization with DNFB through Treg-deficient skin led to enhanced differentiation of IFN-gamma-producing CD8+ T cells in the draining lymph nodes (dLNs). DT-induced ablation of cutaneous Tregs resulted in the increased accumulation of and enhanced CD80/CD86 expressions by FITC+ dendritic cells (DCs) in the dLNs following skin painting with FITC, indicating that Tregs suppressed maturation of hapten-bearing dermal DCs. In addition, we found that IL-10, which was known to inhibit DC maturation, was produced exclusively by Tregs in the skin. Thus, we are currently examining whether IL-10 production from cutaneous Tregs was essential for Treg-mediated suppression of DC maturation. In conclusion, Tregs in the skin are essential for preventing excessive immune responses to percutaneous sensitization by suppressing dermal DC migration and maturation. http://dx.doi.org/10.1016/j.jdermsci.2017.02.191