Preferential accumulation of CD103+ T cells in human livers; its association with extrathymic T cells.
ABSTRACT CD103, a mucosal integrin alphaEbeta7, binds to E-cadherin expressed on hepatocytes and bile duct epithelium in the liver. Although CD103+ T cells are enriched in intestinal intraepithelial lymphocytes, the localization of those cells in the liver is unknown.
We investigated whether CD103+ cells are present in human livers, and how they are associated with the intrahepatic development of T cells by flow cytometry and immunohistochemistry.
Human livers contain significantly (P<0.001) higher percentages of CD103+ cells in CD4+ and CD8+ T cells (25.7+/-13.5 and 27.1+/-19.3%, respectively) than peripheral blood lymphocytes. Moreover, CD103+ cells in the liver, but not in peripheral blood, contained T cells with intermediate expression level of T cell receptor alphabeta. Those cells consist of mostly CD4+ and CD4-CD8- cells, and expressed low level of CD56 and interleukin-2 receptor beta chain in most of the population. These characteristics are distinct from natural killer T cells, which have been thought to be extrathymic T cells in human livers. Moreover, intrahepatic CD103+ cells expressed mRNA for recombination-activating gene-1, -2 and pre T cell receptor-alpha detected by reverse transcription-polymerase chain reaction.
CD103+ T cells are preferentially accumulated in human livers, and those T cells show characteristics of extrathymic T cells.
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ABSTRACT: The goal of this study was to determine the in vivo conditions that promote activation of the (CD4-independent) CD8+ T cell-mediated rejection pathway. We have previously noted that hepatocellular but not islet allografts readily activate this rejection pathway. In the current study, we utilized these two cell transplant models to investigate whether differences in host cell recruitment to the graft site, expression of T-cell activation markers by CD8+ graft infiltrating cells (GICs), and/or development of delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte cell-mediated effector functions could account for the differential transplant outcomes. The collective results demonstrate that recruitment of CD8+ T cells to the site of transplant, CD103 or CD69 expression on CD8+ GICs, and activation of alloreactive DTH responses are insufficient to initiate CD4-independent, CD8-dependent transplant rejection. Instead, rejection by alloreactive (CD4-independent) CD8+ T cells correlated with expression of CD25, CD154 and CD43 by CD8+ GICs, in vitro alloproliferation by recipient CD8+ T cells, and the development of in vivo allospecific cytolytic effector function. These results suggest that tissue-derived factors influence the activation and maturation of (CD4-independent) CD8+ T cells into cytolytic effectors, which correlates with transplant rejection.American Journal of Transplantation 11/2006; 6(10):2268-81. · 6.19 Impact Factor
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ABSTRACT: The relationship between bile duct damage and portal fibrosis in chronic liver diseases remains unclear. This study was designed to show whether human intrahepatic biliary epithelial cells can undergo epithelial-mesenchymal cell transition, thereby directly contributing to fibrogenesis. Primary human cholangiocytes were stimulated with transforming growth factor-beta (TGFbeta) or TGFbeta-presenting T cells and examined for evidence of transition to a mesenchymal phenotype. Liver sections were labelled to detect antigens associated with biliary epithelial cells (cytokeratin 7 and 19 and E-cadherin), T cells (CD8), epithelial-mesenchymal transition (S100A4, vimentin and matrix metalloproteinase-2 (MMP-2)), myofibroblasts (alpha-smooth muscle actin) and intracellular signal-transduction mediated by phosphorylated (p)Smad 2/3; in situ hybridisation was performed to detect mRNA encoding TGFbeta and S100A4. Stimulation of cultured cells with TGFbeta induced the expression of pSmad2/3, S100A4 and alpha-smooth muscle actin; these cells became highly motile. Although normal bile ducts expressed ALK5 (TGFbeta RI), low levels of TGFbeta mRNA and nuclear pSmad2/3, they did not express S100A4, vimentin or MMP-2. However, TGFbeta mRNA and nuclear pSmad2/3 were strongly expressed in damaged ducts, which also expressed S100A4, vimentin and MMP-2. Fibroblast-like cells which expressed S100A4 were present around many damaged bile ducts. Cells in the 'ductular reaction' expressed both epithelial and mesenchymal markers together with high levels of TGFbeta mRNA and pSmad2/3. In conclusion, the cells forming small- and medium-sized bile ducts and the ductular reaction undergo EMT during chronic liver diseases, resulting in the formation of invasive fibroblasts; this process may be driven by a response to local TGFbeta, possibly presented by infiltrating T cells.Laboratory Investigation 03/2008; 88(2):112-23. · 3.96 Impact Factor