The objective of this proposal is to characterize mechanism by which keratinocytes (KC) cooperate with gamma delta T cells to form an immunological defense at the environmental interface. Working hypotheses are that: 1) KC and resident gamma delta T cells play critical roles in maintaining the immunological integrity of skin, 2) certain functions of KC and gamma delta T cells are regulated by locally produced cytokines, and 3) environmental stimuli disrupt this equilibrium by altering these cytokine profiles. Dendritic Epidermal T Cells (DETC), one member of the family of resident epithelial gamma delta T cells in mice, will be studied as a prototypic cutaneous gamma delta T cell. IL-7 and transforming growth factor-Beta (TGFBeta) will be studied as cytokines produced by KC that regulate T cell function, and gamma-interferon (gammaIFN) will be studied as a cytokine produced by T cells that modulates KC function. These hypotheses are derived from observations that: 1) DETC growth is promoted by IL-7 and inhibited by TGFbeta, 2) external stimuli modulate cytokine production in KC (e.g., UVB-induced downregulation of IL-7 MRNA expression and gamma IFN-induced expression of a truncated (2.6 kb) IL-7 transcript, 3) DETC kill skin tumor targets and downregulated alpha/beta T cell-mediate immunity, and 4) gamma delta T cells infiltrate and play effector roles in several human skin disorders.
Specific aims are: 1) To determine the physiological roles of IL-7 and TGFbeta in modulating DETC function. Local IL-7 and TGFBeta concentrations will be altered experimentally [cytokine or mAb injection, IL-7 transgenic mice] and DETC in test will be examined for maturation during the neonatal period, modulation of their cell densities, and killing activities. 2) To study IL-7 and TGFBeta gene regulation in KC: a) modulation of IL-7 or TGFBeta production in KC by environmental and cytokine stimuli [Northern blotting, bioassays]; and b) roles of early immediate genes in this regulation [antisense nucleotide blocking]. 3) To identify the function of a gammaIFN-inducible 2.6 kb IL-7 transcript [cDNA cloning and sequencing, mammalian cell expression]. 4) To characterize in vivo functions of DETC. DETC densities will be manipulated experimentally and skin response to alpha/Beta T cell- mediated attack will be examined. 5) To define mechanisms for the cytotoxic recognition of skin tumors by DETC: a) the role played by 2 B4, a novel molecule that mediates non-MHC-restricted target recognition, including b) regulation of 2B4 expression. The proposed studies should lead to a better understanding of cytokine networks in epidermis, the biology of cutaneous gamma delta T cells, and the pathophysiology of T cell-mediated and neoplastic skin disorders in humans.
| 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 |
| 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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