Tim-3/Galectin-9 Regulate the Homeostasis of Hepatic NKT Cells in a Murine Model of Nonalcoholic Fatty Liver Disease

Zhao Hui Tang, Shuwen Liang, James Potter, Xuan Jiang, Hai Quan Mao, Zhiping Li

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


T cell Ig and mucin domain (Tim)-3 is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. However, little is known about the function of Tim-3/Gal-9 signaling in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) mediated by hepatic NKT cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high-fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti-IL-15R/IL-15 mAb, rIL-15, α-galactosylceramide, and multilamellar liposomes containing Cl2MDP. The expression of Tim-3 and various markers reflecting cell proliferation, activation, cytokine production, and apoptosis was analyzed. Liver histology, steatosis grade, and hepatic triglyceride content were also evaluated. In the liver, Tim-3 + NKT cells are in an activated state, and Gal-9 directly induces Tim-3+ NKT cell apoptosis and contributes to the depletion of NKT cells in dietinduced steatosis. However, Gal-9 also interacts with Tim-3-expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cell function. In summary, the Tim-3/Gal-9-signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation-induced apoptosis and secondary proliferation and, thus, contributes to the pathogenesis of NAFLD.

Original languageEnglish (US)
Pages (from-to)1788-1796
Number of pages9
JournalJournal of Immunology
Issue number4
StatePublished - Feb 15 2013
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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