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-β₯), 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 β£ galactosyl-C18ceramide (β£Gal-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-β₯ 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 β£Gal-C18-Cer administration in wild-type but not in NKT celldeficient mice. Moreover, approximately 50% of Tregs recruited to the liver after β£Gal-C18-Cer administration expressed CXCR3 and CXCR3Ψ Treg recruitment into the liver was significantly inhibited in IFN-β₯ KO mice, and after CXCL10 neutralization. In addition, prevention of CXCR3Ψ Treg recruitment into the liver enhanced inflammatory effector cell recruitment into the liver after β£Gal-C18-Cer treatment. Conclusion: These results show that activated NKT cells can induce the hepatic recruitment of Tregs through a cytokine-tochemokine pathway, which could be relevant in the development of chemokine blocking or NKT cell activating strategies to treat liver diseases. (HEPATOLOGY 2009;49:1267-1276.)
N atural killer T (NKT) cells are innate immune cells that are enriched within the liver and have been associated with the development of liver injury in the setting of hepatitis. 1,2 After activation, NKT cells rapidly secrete large amounts of both Th1 [that is, interferon gamma (IFN-β₯)] and Th2 [interleukin (IL) 4] cytokines. 3 Regulatory T cells (Tregs) are another type of immune regulatory cell that play an important role in controlling inflammatory responses. 4 The anatomical site where Tregs exert their immune suppressing effects include both lymphoid and peripheral organ-specific sites; however, recent evidence suggests that Tregs acting in peripheral nonlymphoid tissues can regulate tissue-specific inflammation. 5,6 Tissue homing of Tregs is very likely controlled by chemokines released by immune or parenchymal cells within an inflamed tissue. [6][7][8][9] Within the normal liver Tregs constitute approximately 0.5% to 1% of the total lymphocyte population. 10 However, the factors controlling Treg migration and retention within the liver, as well as the possible role of Tregs in suppressing the hepatic inflammatory response, have not been well defined.
Tregs and NKT cells are both capable of independently regulating the immune response; however, their roles in controlling and regulating the immune response during inflammation have typically been addressed independently. Recent reports have suggested that important crosstalk can occur between Tregs and NKT cells, al-