Mouse epidermis contains two populations of bone marrow-derived dendritic cells, Langerhans cells (LC) and a second population which expresses relatively large amounts of Thy-1 antigen. These latter cells, termed Thy-1+ dendritic epidermal cells (Thy-1+DEC) constitute 1 to 2% of nucleated epidermal cells. Thy-1+DEC express T3, the invariant tri-molecular portion of the T cell receptor, in non-covalent association with gamma/delta T cell receptor chains, rather than with alpha/beta chains, as occurs on typical peripheral T cells. The classification of Thy-1+DEC as an unique T cell is supported by their failure to express cell surface markers of either helper/inducer (L3T4) or suppressor (Lyt-2) peripheral T cells. Thy-1+ DEC proliferate and excrete IL-2 in response to the mitogen Concanavalin A, and this proliferative capacity has allowed us to derive long term cell lines and clones. Lines and clones mediate non-MHC-restricted cytotoxicity against tumor targets in vitro. In the proposed studies we will: 1. Identify subsets of Thy-1+ DEC by differential expression of phenotypic markers and characterize requirements for proliferation in vitro, with attention to strain-to-strain variations, the effects of different mitogens, and the effects of selected growth factors, including Interleukin 1, Interleukin 3, Interleukin 4, and Granulocyte/Monocyte Colony Stimulating Factor. 2. Develop antigen-specific Thy-1+DEC lines and clones, employing antigens which are relevant to cutaneous inflammatory disorders: allogeneic cells, B16 melanoma, 5C25 ultraviolet radiation-induced fibrosarcoma, and trinitrophenol. 3. Assess the factors which regulate the acquisition of cytotoxic potential by cells derived directly from skin and by lines and clones. 4. Assess the contribution of Thy-1+DEC to the down-regulation of CH responses to trinitrochlorobenzene, employing hapten-derivatized cells administered intravenously. 5. Search for a human homolog of Thy- 1+DEC by in situ hybridization with nucleic acid probes. Ultimately, it is anticipated that these dendritic epidermal cells will be found to represent a distinct lineage of T cells and that their functional attributes will be related to that of the T3+ """"""""double-negative"""""""" lymphocytes which have been derived from peripheral blood and thymus of humans and of mice.
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| 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 |
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| 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 |
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| Matsue, Hiroyuki; Matsue, Keiko; Edelbaum, Dale et al. (2004) New strategy for efficient selection of dendritic cell-tumor hybrids and clonal heterogeneity of resulting hybrids. Cancer Biol Ther 3:1145-51 |
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