Journal
CELL REPORTS
Volume 24, Issue 7, Pages 1830-1841Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.07.036
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Funding
- JSPS KAKENHI [15K19082, 17K15674, 15K09036, 17K08802, 17KT0132]
- National Center for Global Health and Medicine [25-107, 26-110, 29-1008]
- Grants-in-Aid for Scientific Research [17K15674, 17KT0132, 15K19082, 15K09036, 17K08802] Funding Source: KAKEN
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Lnk/Sh2b3 is an adaptor protein that negatively regulates cytokine signaling in lymphohematopoiesis. 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(-/)(-) mice. Moreover, immune cells such as group 1 innate lymphoid cells (G1-ILCs), CD8(+) T cells, and M1 macrophages accumulated in adipose tissue. When Lnk(-/)(-) mice were crossed with Il15(-/- )mice or depleted of G1-ILCs but not CD8(+) T cells, glucose intolerance and adipose inflammation were ameliorated. Lnk(-/)(-) G1-ILCs showed activated phenotypes as well as enhanced reactivity for IL-15, and administration of a JAK inhibitor improved glucose tolerance. Accordingly, a high-fat diet greatly worsened glucose intolerance in Lnk(-/)(-) mice. Thus, Lnk/Sh2b3 controls homeostasis in adipose tissue and reduces the risk of onset of diabetes by regulating the expansion and activation of IL-15-dependent adipose G1-ILCs.
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