IL-15-High-Responder Developing NK Cells Bearing Ly49 Receptors in IL-15(-/-) Mice

信州大学博士（医学）・学位論文・平成24年3月31日授与（甲第910号）・好沢克Originally published in The Journal of Immunology. Yoshizawa, K; Nakajima, S; Notake, T; Miyagawa, SI; Hida, S; Taki, S. 2011. IL-15-High-Responder Developing NK Cells Bearing Ly49 Receptors in IL-15(-/-) Mice . J. Immunol. Vol.187(10): pp5162-pp5169. Copyright (C) 2011 The American Association of Immunologists, Inc.In mice lacking IL-15, NK cell development is arrested at immature stages, providing an opportunity to investigate the earliest developing NK cells that would respond to IL-15. We show in this study that immature NK cells were present in the spleen as well as bone marrow (BM) and contained IL-15-high-responder cells. Thus, mature NK cells were generated more efficiently from IL-15(-/-) than from control donor cells in radiation BM chimeras, and the rate of IL-15-induced cell division in vitro was higher in NK cells in the spleen and BM from IL-5(-/-) mice than in those from wild-type mice. Phenotypically, NK cells developed in IL-15(-/-) mice up to the minor but discrete CD11b(-)CD27(+)DX5(hi)CD51(dull)CD127(dull)CD122(hi) stage, which contained the majority of Ly49G2(+) and D+ NK cells both in the spleen and BM. Even among wild-type splenic NK cells, IL-15-induced proliferation was most prominent in CD11b(-)DX5(hi) cells. Notably, IL-15-mediated preferential expansion (but not conversion from Ly49(-) cells) of Ly49(+) NK cells was observed in vitro only for NK cells in the spleen. These observations indicated the uneven distribution of NK cells of different developing stages with variable IL-15 responsiveness in these lymphoid organs. Immature NK cells in the spleen may contribute, as auxiliaries to those in BM, to the mature NK cell compartment through IL-15-driven extramarrow expansion under steady-state or inflammatory conditions. The Journal of Immunology, 2011, 187: 5162-5169.ArticleJOURNAL OF IMMUNOLOGY. 187(10):5162-5169 (2011)journal articl

Prostaglandin D2 Reinforces Th2 Type Inflammatory Responses of Airways to Low-dose Antigen through Bronchial Expression of Macrophage-derived Chemokine

PGD2, a lipid mediator released from mast cells, is known to participate in allergic reactions. However, the mechanism by which PGD2 contributes to such reactions remains unclear. We established a novel experimental model of asthma that permitted direct assessment of the role of PGD2 in airway inflammation. Antigen-sensitized mice were exposed to aerosolized prostaglandin D2 (PGD2) 1 d before challenge with low-dose aerosolized antigen. Not only the numbers of eosinophils, lymphocytes, and macrophages but also the levels of IL-4 and IL-5 in bronchoalveolar lavage fluid were higher in PGD2-pretreated mice than in control mice. The expression of macrophage-derived chemokine (MDC), a chemoattractant for Th2 cells, was greater in PGD2-pretreated mice than in control. Injection of anti-MDC antibody into PGD2-pretreated mice markedly inhibited inflammatory cell infiltration as well as Th2 cyto-kine production after antigen challenge. These results indicate that PGD2 accelerates Th2 type inflammation by induction of MDC. Our results suggest that this mechanism may play a key role in the development of human asthma and that MDC might be a target molecule for therapeutic intervention

IL-15 inhibits pre-B cell proliferation by selectively expanding Mac-1+B220+ NK cells

ArticleBIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS. 369(4): 1139-1143 (2008)journal articl

IL-15–High-Responder Developing NK Cells Bearing Ly49 Receptors in IL-15 −/−

信州大学博士（医学）・学位論文・平成24年3月31日授与（甲第910号）・好沢克Originally published in The Journal of Immunology. Yoshizawa, K; Nakajima, S; Notake, T; Miyagawa, SI; Hida, S; Taki, S. 2011. IL-15-High-Responder Developing NK Cells Bearing Ly49 Receptors in IL-15(-/-) Mice . J. Immunol. Vol.187(10): pp5162-pp5169. Copyright (C) 2011 The American Association of Immunologists, Inc.In mice lacking IL-15, NK cell development is arrested at immature stages, providing an opportunity to investigate the earliest developing NK cells that would respond to IL-15. We show in this study that immature NK cells were present in the spleen as well as bone marrow (BM) and contained IL-15-high-responder cells. Thus, mature NK cells were generated more efficiently from IL-15(-/-) than from control donor cells in radiation BM chimeras, and the rate of IL-15-induced cell division in vitro was higher in NK cells in the spleen and BM from IL-5(-/-) mice than in those from wild-type mice. Phenotypically, NK cells developed in IL-15(-/-) mice up to the minor but discrete CD11b(-)CD27(+)DX5(hi)CD51(dull)CD127(dull)CD122(hi) stage, which contained the majority of Ly49G2(+) and D+ NK cells both in the spleen and BM. Even among wild-type splenic NK cells, IL-15-induced proliferation was most prominent in CD11b(-)DX5(hi) cells. Notably, IL-15-mediated preferential expansion (but not conversion from Ly49(-) cells) of Ly49(+) NK cells was observed in vitro only for NK cells in the spleen. These observations indicated the uneven distribution of NK cells of different developing stages with variable IL-15 responsiveness in these lymphoid organs. Immature NK cells in the spleen may contribute, as auxiliaries to those in BM, to the mature NK cell compartment through IL-15-driven extramarrow expansion under steady-state or inflammatory conditions. The Journal of Immunology, 2011, 187: 5162-5169.ArticleJOURNAL OF IMMUNOLOGY. 187(10):5162-5169 (2011)journal articl

Conditional Deletion of TAK1 in T Cells Reveals a Pivotal Role of TCRαβ⁺ Intraepithelial Lymphocytes in Preventing Lymphopenia-Associated Colitis

<div><p>The kinase TAK is required for the development of conventional and regulatory T cells. We previously reported that mice with conditional deletion of TAK1 in T cells (Lck-cre:TAK1^fl/fl mice) exhibited severe T lymphopenia, and were nevertheless predisposed to spontaneous colitis with unknown etiology. Here we focused on the immunopathological mechanism in colitic Lck-cre:TAK1^fl/fl mice. We found that ‘leaky’ CD4⁺ T cells retaining TAK1 acquired inflammatory phenotypes that contribute to disease onset in Lck-cre:TAK1^fl/fl mice. Furthermore, the gut microbiota-triggered signaling was also a key event leading to the pathogenesis. We discovered that Lck-cre:TAK1^fl/fl mice were almost completely devoid of TCRαβ⁺CD8α⁺ intestinal intraepithelial lymphocytes (IELs) and this was largely due to the developmental defect of the thymic precursors by TAK1 deficiency. Remarkably, transfer of TCRαβ⁺CD8α⁺ IELs from wild-type mice ameliorated colitis in Lck-cre:TAK1^fl/fl mice. Taken together, our current study highlighted the emerging role of TAK1 in configuring the gut-specialized T cell subset, which regulates mucosal homeostasis under lymphopenic conditions.</p></div