Langerhans cells (LC) ordinarily deliver activation signals to T cells. We hypothesized that LC genetically modified to over-express CD95L (Fas ligand) termed """"""""killer"""""""" LC, would deliver apoptotic signals to T cells upon antigen-specific interaction. To test this, we introduced CD95L cDNA into our LC line XS106 (derived from A/J mice) and selected a stable clone (XS 10-6-CD95L) that expressed abundant surface CD95L. This killer LC clone, when pulsed with ovalbumin (OVA), triggered apoptosis of OVA-reactive CD4+ T cells in vitro by an antigen-specific and CD95L-dependent mechanism. OVA-pulsed killer LC, when injected into A/J mice before or after sensitization, suppressed ear swelling responses to DNFB. Importantly, OVA-pulsed killer LC suppressed OVA responses, but not responses to the irrelevant antigen HEL, whereas HEL- pulsed killer LC inhibited only the HEL responses, establishing antigen- specificity. We will define mechanisms, under the new hypothesis that killer LC suppress diverse immunological responses by triggering apoptosis of putative effector T cells that recognize respective antigens. Specifically, we will study the impact of killer LC using five-established animal models: 1) Delayed type hypersensitivity: We will inject OVA- pulsed killer LC before or after sensitization to study the impact of CD4+ effect T cells and memory T cells, the fate of effector cells (adoptive transfer of OVA-reactive, naive CD4+ T cells from the D011.10 transgenic mice), and the critical timing for cytotoxic interaction of killer LC with T cells (drug-inducible suicide system). 2) Contact hypersensitivity. We will inject DNFB-pulsed killer LC before or after sensitization to study the impact of CD8+ effector T cells and on Th2-like regulatory T cells, killer LC interaction with CD8+ T cells and antigen- specificity. 3) Th2-biased immune responses. Mice will be sensitized epicutaneously with an OVA-absorbed """"""""patch"""""""" to produce OVA-specific IgE and IgG1 antibodies and atopic dermatitis-like skin lesions. We will inject OVA-pulsed killer LC to study the impact on Th2-biased effector and helper T cells and """"""""therapeutic"""""""" efficacy for skin lesions. 4) Experimental autoimmune myocarditis. Mice will be sensitized with cardiac myosin (CM) to produce autoimmune myocarditis. We will inject CM-pulsed killer LC to study the impact on CD4+ pathogenic T cells that recognize tissue-specific autoantigen, the fate of pathogenic T cells, and therapeutic efficacy and safety. 5) Skin graft rejection. We will study the impact of killer LC and """"""""killer LC hybrids"""""""" on allo-reactive CD4+ and CD8+ T cells, which are ordinary activated via """"""""direct"""""""" and """"""""indirect"""""""" pathways. These studies will form the framework for establishing an entirely new immunosuppressive therapy for inflammatory skin diseases, the therapy designed to eliminate selectively the effector T cells that recognize pathogenic antigens (e.g., haptens, allergens, autoantigens, and alloantigens).
| Matsushima, Hironori; Ogawa, Yasushi; Miyazaki, Toru et al. (2010) Intravital imaging of IL-1beta production in skin. J Invest Dermatol 130:1571-80 |
| Matsushima, Hironori; Takashima, Akira (2010) Bidirectional homing of Tregs between the skin and lymph nodes. J Clin Invest 120:653-6 |
| Mayuzumi, Nobuyasu; Matsushima, Hironori; Takashima, Akira (2009) IL-33 promotes DC development in BM culture by triggering GM-CSF production. Eur J Immunol 39:3331-42 |
| Matsushima, Hironori; Tanaka, Hiroaki; Mizumoto, Norikatsu et al. (2009) Identification of crassin acetate as a new immunosuppressant triggering heme oxygenase-1 expression in dendritic cells. Blood 114:64-73 |
| Mizumoto, Norikatsu; Tanaka, Hiroaki; Matsushima, Hironori et al. (2007) Colchicine promotes antigen cross-presentation by murine dendritic cells. J Invest Dermatol 127:1543-6 |
| Ward, Brant R; Jester, James V; Nishibu, Akiko et al. (2007) Local thermal injury elicits immediate dynamic behavioural responses by corneal Langerhans cells. Immunology 120:556-72 |
| Ogawa, Yasushi; Mizumoto, Norikatsu; Tanaka, Hiroaki et al. (2006) Identification of novel pharmacological activities of an antifungal agent, nystatin, to promote dendritic cell maturation. J Invest Dermatol 126:349-53 |
| Mizumoto, Norikatsu; Hui, Francis; Edelbaum, Dale et al. (2005) Differential activation profiles of multiple transcription factors during dendritic cell maturation. J Invest Dermatol 124:718-24 |
| Mizumoto, Norikatsu; Gao, Jimin; Matsushima, Hironori et al. (2005) Discovery of novel immunostimulants by dendritic-cell-based functional screening. Blood 106:3082-9 |
| Kusuhara, Masahiro; Matsue, Hiroyuki (2005) Limitations of CD95 ligand-transduced killer dendritic cells to prevent graft rejections. Exp Dermatol 14:273-80 |
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