29 In this context, Tregs are likely to have synergistic regulatory effects on different arms of the immune system based on the stages of bile duct injury. Collectively, our in vitro and in vivo studies in a well-established murine model of BA provide compelling evidence that Treg deficiency leads to unopposed DC-dependent costimulation and aberrant activation of effector

T-lymphocytes in the neonatal liver conferring susceptibility to BA. Furthermore, our study revealed cellular and molecular candidates for future investigations to elucidate whether costimulatory blockade of T-cell activation by targeting Tregs or Treg-dependent pathways may prevent progression of bile click here duct obstruction in BA. Additional Supporting Information may be found in the online version of this GDC-0199 research buy article. “
“In a recent article in HEPATOLOGY, Kremer et al. explored the association between steatosis, cytokines, and natural killer T (NKT) cell numbers. Elegant experiments suggest that increased interleukin-12 (IL12) secretion, in part by Kupffer

cells, leads to NKT depletion in mice and humans with liver steatosis.1 Recent data suggests that steatosis (consisting mainly of triglycerides) per se is a benign condition and reflects the body’s strategy to cope with excessive fatty acid flux.2 Progressive fatty liver disease that develops in a minority of individuals may stem from MCE dysregulated repair responses.3 The hedgehog pathway has been shown to modulate such responses, and overactivation of the hedgehog pathway leads to fibrogenesis. Furthermore, exposure of primary liver NKT cells to increasing concentrations of Sonic hedgehog, a hedgehog ligand, promotes NKT cell viability and proliferation, and enhances IL13 (a T helper 2 [Th2]cytokine) secretion.4 Mice with excessive hedgehog signaling also harbor increased NKT cells and develop increased

fibrosis in diet-induced nonalcoholic steatohepatitis (W. K. Syn et al., manuscript submitted). Indeed, Tajiri et al. noted increased NKT numbers among individuals with greater nonalcoholic steatohepatitis activity scores.5 In contrast to benign hepatic steatosis, there is increasing data supporting the concept that NKT cells accumulate with progressive fatty liver disease. In this study, NKT cell depletion was associated with elevated IL12 levels; conversely, NKT population was preserved in IL12 knockout mice. As suggested, additional factors are likely to be involved in determining the size of the hepatic NKT population. For example, NKT cells express cysteine-X-cysteine receptor 3 (CXCR3) and CXCR6; recruitment of NKT cells in steatotic liver is likely to be regulated by their associated ligands. In addition, because NKT cell viability is modulated by IL15,6 it would be important to determine if expression of IL15 alters with steatosis.