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Natural killer T cells regulate the homing of chemokine CXC receptor 3‐positive regulatory T cells to the liver in mice
Author(s) -
SantodomingoGarzon Tania,
Han Jinglan,
Le Tai,
Yang Yang,
Swain Mark G.
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.22761
Subject(s) - cxcr3 , cxcl10 , natural killer t cell , immunology , biology , chemokine , t cell , natural killer cell , interferon gamma , cytokine , immune system , microbiology and biotechnology , chemokine receptor , cytotoxic t cell , biochemistry , in vitro
Natural killer T (NKT) cells and regulatory T cells (Tregs) are both found within the liver and are known to exhibit immune regulatory functions. Hepatic NKT cells are activated early during inflammatory responses and release cytokines, including interferon gamma (IFN‐γ), which we speculated could regulate Treg recruitment to the liver. To examine this, we treated C57BL/6 mice with a specific NKT cell activating ligand α galactosyl‐C18‐ceramide (αGal‐C18‐Cer) and examined the hepatic recruitment of Tregs. We found a time‐dependant increase in the hepatic recruitment of Tregs after NKT cell activation, which was absent in NKT cell–deficient mice. Most recruited Tregs expressed interleukin (IL) 10, and to a lesser extent transforming growth factor beta (TGF‐β). Because IFN‐γ induces the production of chemokine (C‐X‐C motif) ligand 10 (CXCL10), and Tregs can express the cognate receptor for CXCL10 (that is, CXCR3), we considered that CXCL10 might mediate the hepatic recruitment of Tregs after NKT cell activation. Hepatic CXCL10 levels were markedly increased after αGal‐C18‐Cer administration in wild‐type but not in NKT cell–deficient mice. Moreover, approximately 50% of Tregs recruited to the liver after αGal‐C18‐Cer administration expressed CXCR3 and CXCR3+ Treg recruitment into the liver was significantly inhibited in IFN‐γ KO mice, and after CXCL10 neutralization. In addition, prevention of CXCR3+ Treg recruitment into the liver enhanced inflammatory effector cell recruitment into the liver after αGal‐C18‐Cer treatment. Conclusion: These results show that activated NKT cells can induce the hepatic recruitment of Tregs through a cytokine‐to‐chemokine pathway, which could be relevant in the development of chemokine blocking or NKT cell activating strategies to treat liver diseases. (H EPATOLOGY 2009.)