Novel control mechanism by autoimmune disease-related gene Lnk/Sh2b3 in diabetic pathogenesis

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K19082
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Mori Taizo 国立研究開発法人国立国際医療研究センター, 免疫制御研究部, 研究員 (40625307)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 2型糖尿病 / 免疫学 / シグナル伝達 / サイトカイン / 自己免疫疾患関連遺伝子

Outline of Final Research Achievements

Lnk/Sh2b3 is an adaptor protein that negatively regulates cytokine signaling in lymphopoiesis. A missense variant within the LNK/SH2B3 gene has been reported to be a risk variant for several autoimmune diseases including diabetes. We found that glucose tolerance and insulin responses were impaired in Lnk KO mice. Moreover, immune cells such as group 1 innate lymphoid cells and M1 macrophages accumulated in adipose tissues. When Lnk KO mice were crossed with Il15 KO mice or depleted of G1-ILCs but not CD8+ T cells, glucose intolerance and adipose inflammation were ameliorated. Lnk KO G1-ILCs showed activated phenotypes as well as enhanced reactivity for IL-15, and administration of a JAK3 inhibitor improved glucose tolerance. Thus, Lnk/Sh2b3 controls homeostasis in adipose tissues and reduces the risk for onset of diabetes by regulating the expansion and activation of IL-15-dependent adipose G1-ILCs.

Free Research Field

実験病理学