Immunoregulatory function of Lnk/Sh2b3, a common risk factor gene for immune, hematopoietic and cardiovascular diseases

• Project/Area Number: 25293097
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Takaki Satoshi 国立研究開発法人国立国際医療研究センター, 研究所, 免疫制御研究部長 (10242116)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed(Fiscal Year 2015)
• Budget Amount: ¥16,640,000 (Direct Cost : ¥12,800,000、Indirect Cost : ¥3,840,000); Fiscal Year 2015 : ¥5,330,000 (Direct Cost : ¥4,100,000、Indirect Cost : ¥1,230,000); Fiscal Year 2014 : ¥5,330,000 (Direct Cost : ¥4,100,000、Indirect Cost : ¥1,230,000); Fiscal Year 2013 : ¥5,980,000 (Direct Cost : ¥4,600,000、Indirect Cost : ¥1,380,000)
• Keywords: 疾患関連遺伝子 / 自己免疫 / 高血圧 / 糖尿病 / シグナル伝達 / 骨髄増殖性疾患 / 免疫学

Outline of Final Research Achievements

Mutations in the LNK/SH2B3 gene are found in myeloproliferative disease patients, and LNK/SH2B3 polymorphisms have been reported to be associated with several autoimmune diseases and cardiovascular diseases. The intracellular adaptor Lnk/Sh2b3 regulates cytokine signals that control lymphohematopoiesis, However, the functions of Lnk/Sh2b3 related to autoimmune inflammation or cardiovascular dysfunction have not been understood. We have revealed that the ability of DCs to support Th1 response was altered by Lnk-deficiency. We have shown that Lnk/Sh2b3 plays a role in preventing pathogenic expansion and activation of CD8+ T cells leading to intestinal tissue damage in Lnk-/- mice. IFN-gamma-producing CD8+ T cells were increased in kidney and arteries, resulting in increased susceptibility for hypertension. We also found that Lnk-/- mice showed impaired glucose tolerance that was largely depend on the abnormality of hematopoietic cells.

Research Products

• [Int'l Joint Research] ヴァンダービルト大学/アトランタ大学/国立心肺血液研究所(アメリカ合衆国)
• [Journal Article] Interferon-gamma Constrains Cytokine Production of Group 2 Innate Lymphoid Cells (2016)
  • Author(s): Kudo, F. Ikutani, M. Seki, Y. Otsubo, T. Kawamura, Y. I. Dohi, T. Oshima, K. Hattori, M. Nakae, S. Takatsu, K. Takaki, S.
  • Journal Title: Immunology Volume : 147 Pages : 21-29
  • DOI: 10.1111/imm.12537
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lymphocyte adaptor protein LNK deficiency exacerbates hypertension and end-organ inflammation. (2015)
  • Author(s): Saleh MA, McMaster WG, Wu J, Norlander AE, Funt SA, Thabet SR, Kirabo A, Xiao L, Chen W, Itani HA, Michell D, Huan T, Zhang Y, Takaki S, Titze J, Levy D, Harrison DG, Madhur MS.
  • Journal Title: J Clin Invest. Volume : 125 Pages : 1189-1202
  • DOI: 10.1172/jci76327
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lnk prevents inflammatory CD8+ T-cell proliferation and contributes to intestinal homeostasis. (2014)
  • Author(s): Katayama H., Mori T., Seki Y., Anraku M., Iseki M., Ikutani M., Iwasaki Y., Yoshida N., Takatsu K., Takaki S.
  • Journal Title: European Journal of Immunology Volume : 44 Pages : 1622-1632
  • DOI: 10.1002/eji.201343883
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lnk/Sh2b3 controls the production and function of dendritic cells, regulates the induction of IFN-gamma-producing T cells. (2014)
  • Author(s): Mori T., Iwasaki Y., Seki Y., Iseki M., Katayama H., Yamamoto K., Takatsu K., Takaki S.
  • Journal Title: The Journal of Immunology Volume : 193 Pages : 1728-36
  • DOI: 10.4049/jimmunol.1303243
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Adipose Natural Regulatory B Cells Negatively Control Adipose Tissue Inflammation. (2014)
  • Author(s): Nishimura S, Manabe I, Takaki S, Nagasaki M, Otsu M, Yamashita H, Sugita J, Yoshimura K, Eto K, Komuro I, Kadowaki T, Nagai R.
  • Journal Title: Cell metabolism. Volume : in press Pages : 759-766
  • DOI: 10.1016/j.cmet.2013.09.017
  • Peer Reviewed
• [Journal Article] Nov/CCN regulates long term repopulation activity of murine hematopietic stem cells via integrin αvβ3. (2014)
  • Author(s): Ishihara, J., Umemoto, T., Yamato, M., Shiratsuchi, Y., Takaki, S., Petrich, B.G., Nakauchi, H., Eto, K., Kitamura, T., and Okano T.
  • Journal Title: Int. J. Hematol. Volume : 99 Pages : 393-406
  • DOI: 10.1007/s12185-014-1534-x
  • Peer Reviewed
• [Journal Article] Generation of engraftable hematopoietic stem cells from induced pluripotent stem cells by way of teratoma formation. (2013)
  • Author(s): Suzuki N, Yamazaki S, Yamaguchi T, Okabe M, Masaki H, Takaki S, Otsu M, Nakauchi H.
  • Journal Title: Mol Ther. Volume : 21 Pages : 1424-31
  • DOI: 10.1038/mt.2013.71
  • Peer Reviewed
• [Journal Article] TWEAK/Fn14 pathway promotes a T helper 2-type chronic colitis with fibrosis in mice (2013)
  • Author(s): Son A, Oshio T, Kawamura YI, Hagiwara T, Yamazaki M, Inagaki-Ohara K, Okada T, Wu P, Iseki M, Takaki S, Burkly LC, Dohi T
  • Journal Title: Mucosal Immunology Volume : 6 Pages : 1131-1142
  • DOI: 10.1038/mi.2013.10
  • Peer Reviewed
• [Presentation] An autoimmune disease-associated gene, Lnk/Sh2b3 controls inflammation in adipose tissue and reduces the risk for onset of diabetes. (2015)
  • Author(s): Mori T, Yamazaki N, Takaki S.
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] Inhibitory effects of interferon-γ on cytokine production in group 2 innate lymphoid cells. (2015)
  • Author(s): Kudo F, Takaki S.
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] Germinal center B cell survival and optimal IgE production are controled by Lnk/Sh2b family adaptor protein Aps/Sh2b2. (2015)
  • Author(s): Iseki M, Kudo F, Takaki S.
  • Organizer: 第44回 日本免疫学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] Lnk/Sh2b3 adaptor protein controls cytokine responses of dendritic cells, and regulates the induction of IFN-γ-producing T cells. (2014)
  • Author(s): Mori T, Iseki M, Takaki S.
  • Organizer: 第43回 日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] IgM+ plasma cells contribute to the sufficient production of IgG by secreting IL-10 and IL-13. (2014)
  • Author(s): Yamazaki N, Takaki S.
  • Organizer: 第43回 日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Lnk/Sh2b family adaptor protein Aps/Sh2b2 in B cells contributes to germinal center B cell survival and optimal IgE production in vivo. (2014)
  • Author(s): Iseki M, Kudo F, Takaki S.
  • Organizer: 第43回 日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Suppression of cytokine production from group 2 innate lymphoid cells by interferon-γ. (2014)
  • Author(s): Kudo F, Seki Y, Takaki S.
  • Organizer: 第43回 日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Lnk/Sh2b3, an intracellular adaptor associated with celiac disease and autoimmune diabetes, regulates accumulation of inflammatory T cells and prevents intestinal villous atrophy. The 15th International Congress of Immunology. (2013)
  • Author(s): Mori T, Katayama H, Iwasaki Y, Seki Y, Iseki M, Ikutani M, Yoshida N, Takatsu K, Takaki S.
  • Organizer: The 15th International Congress of Immunology
  • Place of Presentation: Milan, Italy
• [Presentation] Lnk/Sh2b3 adaptor protein prevents the accumulation of inflammatory CD8+ T cells and intestinal villous atrophy. (2013)
  • Author(s): Seki Y, Katayama H, Mori T, Iseki M, Takaki S.
  • Organizer: 第42回 日本免疫学会学術集会
  • Place of Presentation: 千葉
• [Presentation] An autoimmune disease-associated gene, Lnk/SH2B3 controls production and functions of DC subsets and regulates inflammatory T cell differentiation. (2013)
  • Author(s): Mori T, Seki Y, Iwasaki Y, Yamazaki-Suzuki N, Iseki M, Takaki S.
  • Organizer: 第42回 日本免疫学会学術集会
  • Place of Presentation: 千葉
• [Presentation] IgE production and germinal center formation are regulated by the adaptor protein Aps/Sh2b2 in B cells. (2013)
  • Author(s): Iseki M, Kudo F, Takaki S.
  • Organizer: 第42回 日本免疫学会学術集会
  • Place of Presentation: 千葉