|Professor||Koetsu OGASAWARA,DDS, Ph.D|
Natural killer cells are critical for both innate and adaptive immunity. NK cells play important roles in elimination of virally infected cells and tumors. NK cell functions are regulated by the opposing signals from activating or inhibitory receptors. Our laboratory has focused on activating and inhibitory receptors on NK cells and T cells. Recently, we found that NKG2D, an activating receptor, are important for viral immunity, tumor immunity and the development of autoimmune diabetes. Therefore, we will explore that the molecular mechanisms underlying recognition of NK cells and T cells against target cells in viral immunity, tumor immunity, autoimmunity and allergy.
Patients of metal allergy are greatly increased because many people wear metal accessories and jewelleries. It has been thought that the metal allergy is classified under Type IV allergic reaction which is mediated by T cells. However, the molecular mechanisms underlying allergic reactions to metal are still unknown. To investigate the molecular mechanisms of metal allergy we generated a new mouse model. We found that bacterial components, especially lipopolysaccaride, trigger allergic reaction to metal. Our mouse model of metal allergy is highly evaluated by the news of Nature (2007). We would like to obtain novel insights using the models for metal allergy in future.
NKG2D is an activating receptor on NK cells that has been implicated in immunity against tumors and microbial pathogens. Interestingly, NKG2D ligands are widely expressed on malignant tumors. We found that the interaction of NKG2D ligands and NKG2D on NK cells induced dysfunction of activated NK cells. Initial interactions between NK cells and NKG2D ligand bearing cells may trigger killing and cytokine production. However, NKG2D ligands expressed on tumors induce down modulation of NKG2D by prolonged exposure to ligands. This has implications in the context of tumor development because secretion of soluble NKG2D ligands by tumors or prolonged exposure of NK cells to ligand-bearing tumors may render them dysfunctional. This may contribute to tumor escape from NK cell and CD8+T cell immune surveillance (Immunity 2003).
Type I diabetes (TID) is an autoimmune disease in which insulin-producing beta cells in pancreatic islets are destroyed by autoreactive T cells. The nonobese diabetic (NOD) mouse is widely studied as a model of human TID. Recently, we show that one of NKG2D ligands, RAE-1, is present in prediabetic pancreas islets of NOD mice and that autoreactive CD8+T cells infiltrating the pancreas express NKG2D. Treatment with an anti-NKG2D antibody during the prediabetic stage completely prevented disease by impairing the expansion and function of autoreactive CD8+ T cells. These findings demonstrate that NKG2D is essential for disease progression and provide a new therapeutic target for autoimmune type I diabetes (Immunity 2004).
Selected Publication （Selected 25 papers）
I. Original papers:
- Mori T, Ishida K, Mukumoto S, Yamada Y, Imokawa G, Kabashima K, Bito T, Nakamura M, Ogasawara K, Tokura Y. Comparison of skin barrier function and sensory nerve electric current perception threshold between IgE-high extrinsic and IgE-normal intrinsic types of atopic dermatitis Br J Dermatol in press
- Vilarinho S, Ogasawara K, Nishimura S, Lanier LL, Baron JL. (2007) Blockade of NKG2D on NKT cells prevents hepatitis and the acute immune response to hepatitis B virus. Proc Natl Acad Sci U S A. 104(46):18187-92. Cited:28
- Ogasawara K, Benjamin J, Takaki R, Phillips J H, Lanier L L. (2005) Function of NKG2D in natural killer cell-mediated rejection of mouse bone marrow grafts. Nat Immunol 6(9):938-945. Cited: 60
- Ogasawara K., Hamerman J. A., Ehrlich L.R., Jordan H., Bluestone J. A., Lanier L. L. (2004) NKG2D blockade prevents autoimmune diabetes in NOD mice. Immunity 20: 757-767. Cited:120
- Hamerman J.A., Ogasawara K., Lanier L.L. (2004) Toll-like receptor signaling in macrophages induces ligands for the NKG2D receptor. J Immunol 172 (4) : 2001-2005 Cited:76
- Ogasawara K., Hamerman J. A., Hsin H., Chikuma S, Jordan H., Chen T., Pertel T., Carnaud C., Bluestone J. A., Lanier L. L. (2003) Impairment of NK cell function by NKG2D modulation in NOD mice. Immunity 18: 41-51. Cited:116
- Lodoen, M., Ogasawara K, Hamerman J.A., Arase H., Houchins J. P., Mocarski E.S., and Lanier L.L. (2003). NKG2D-mediated NK cell protection against cytomegalovirus is impaired by gp40 modulation of RAE-1 molecules. J. Exp. Med 197: 1245-1253. Cited:125
- Zompi S, Hamerman J.A, Ogasawara K, Schweighoffer E, Tybulewicz V.L.J, Di Santo JP, Lanier LL, and Colucci F. (2003) The NKG2D receptor triggers cytotoxicity but not cytotokine production in mouse Natural killer cells lacking DAP12 or Syk tyrosine kinases. Nat Immunol 4: 565-572. Cited:101
- Ogasawara, K., Yoshinaga, S. K., Lanier, L. L. (2002) Inducible Costimulator Costimulates Cytotoxic Activity and IFN-gamma Production in Activated Murine NK Cells. J Immunol 169: 3676-3685 Cited:38
- Sato K, Hida S, Takayanagi H, Yokochi T, Kayagaki N, Takeda K, Yagita H, Okumura K, Tanaka N Taniguchi T, Ogasawara K. (2001) Antiviral response by natural killer cells through TRAIL gene induction by IFN-α/β Eur J Immunol 11:3138-3146 Cited:105
- Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Katsuki M, Noguchi S, Tanaka N, Taniguchi T.(2000) Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-α/β gene induction. Immunity 13:539-548 Cited:447
- Nakagawa T, Setou M, Seog D, Ogasawara K, Dohmae N, Takio K, Hirokawa N. (2000) A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell 103:569-581 Cited:130
- Hida S*, Ogasawara K*, Sato K, Abe M, Takayanagi H, Yokochi T, Sato T, Hirose S, Shirai T, Taki S, Taniguchi T. (2000) CD8+ T cell-mediated skin disease in mice lacking IRF-2, the transcriptional attenuator of interferon-a/b signaling. Immunity 13:643-655. *The first two authors are equal contributors. Cited:101
- Takayanagi H, Ogasawara K, Hida S, Chiba T, Murata S, Sato K, Takaoka A, Yokochi T, Oda H, Tanaka K, Nakamura K, Taniguchi T. (2000) T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408:600-605 Cited:413
- Ogasawara K, Hida S, Azimi N, Tagaya Y, Sato T, Yokochi-Fukuda T, Waldmann T.A, Taniguchi T, Taki S. (1998). Requirement for IRF-1 in the microenvironment supporting natural killer cell development. Nature 391: 700-703 Cited:213
- Ogasawara K, Takeda K, Hashimoto W,Satoh M, Okuyama R, Yanai N, Obinata M, Kumagai K, Takada H, Hiraide H, Seki S. (1998). Involvement of NK1.1+T cells and their IFN-g production in the generalized Shwartzman reaction. J Immunol 160 (7): 3522-3527 Cited:98
- Fujii H, Ogasawara K, Otsuka H, Suzuki M, Yamamura K, Yokochi T, Miyazaki T, Suzuki H, Mak TW, Taki S, Taniguchi T. (1998). Functional dissection of the cytoplasmic subregions of the IL-2 receptor bc chain in primary lymphocyte populations. EMBO J 17(22):6551-6557 Cited:49
- Taki S, Sato T, Ogasawara K, Fukuda T, Sato M, Hida S, Suzuki G, Mitsuyama M, Shin EH, Kojima S, Taniguchi T, Asano Y. (1997). Multistage regulation of Th1-type immune responses by the transcription factor IRF-1. Immunity 6 (6):673-679 Cited:210
- Takahashi M*, Ogasawara K*, Takeda K, Hashimoto W, Sakihara H, Kumagai K, Anzai R, Satoh M, Seki S. (1996). LPS induces NK1.1+ αβ T cells with potent cytotoxicity in the liver of mice via production of IL-12 from Kupffer cells. J Immunol 156(7):2436-2442 *The first two authors are equal contributors. Cited:102
- Takeda K, Seki S, Ogasawara K, Anzai R, Hashimoto W, Sugiura K, Takahashi M, Satoh M, Kumagai K. (1996). Liver NK1.1+ CD4+ αβ T cells activated by IL-12 as a major effector in inhibition of experimental tumor metastasis. J Immunol 156(9):3366-3373 Cited:167
- Satoh M, Seki S, Hashimoto W, Ogasawara K, Kobayashi T, Kumagai K, Matsuno S, Takeda K. (1996). Cytotoxic αβ or γδ T cells with a natural killer cell marker, CD56, induced from human peripheral blood lymphocytes by a combination of IL-12 and IL-2. J Immunol 157(9):3886-3892 Cited:89
- Hashimoto W, Takeda K, Anzai R, Ogasawara K, Sakihara H, Sugiura K, Seki S, Kumagai K. (1995). Cytotoxic NK1.1 Ag+ αβ T cells with intermediate TCR induced in the liver of mice by IL-12. J Immunol 154(9):4333-4340 Cited:222