The Tim-3 ligand galectin-9 negatively regulates CD8 + alloreactive T cell and prolongs survival of skin graft

Abstract

CD8 + alloreactive T cells are the key mediators of accelerated rejection. Vigorous CD8 + alloreactive T cells responses against alloantigens, which is the main effector mechanism in acute allograft rejection, has been well described. But the molecular mechanisms to dampen activated CD8 + T cells are largely unknown. On the other hand, Tim-3 is a molecule expressed on terminally differentiated CD4 + Th1 cells. Engaging Tim-3 with its ligand galectin-9 causes an inhibitory signal, resulting in apoptosis of Th1 cells and negatively regulates Th1 type immunity. However, the question whether CD8 + T cells express surface molecular Tim-3 has not been fully elucidated. In this study, we have investigated which CD8 + subset express molecular Tim-3 by flow cytometric assay. In addition, cytotoxic assay was applied to analyze whether CD8 + alloreactive T cells were sensitive to galectin-9 induced apoptosis. Here, our results demonstrated that Tim-3 was expressed on activated CD8 + alloreactive T cells (CD8 +CD44 highCD62L low), but not expressed on naïve CD8 + T cells. Furthermore, alloreactive CD8 + cytotoxic T cells were sensitive to galectin-9 induced apoptosis both in vitro and vivo, resulting in attenuation of CD8 + alloreactive T cells mediated cytotoxicity and prolonged survival of skin graft.