deletion of pkbαakt1 affects thymic development删除pkbαakt1影响胸腺发育.pdfVIP

Deletion of PKBa/Akt1 Affects Thymic Development 1 2 1 1 ¨ 2 1 Elisabeth Fayard , Jason Gill , Magdalena Paolino , Debby Hynx , Georg A. Hollander , Brian A. Hemmings * 1 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland, 2 Pediatric Immunology, Center for Biomedicine, Department of Clinical- Biological Sciences, The University of Basel, The University Children’s Hospital, Basel, Switzerland Background. The thymus constitutes the primary lymphoid organ for the majority of T cells. The phosphatidyl-inositol 3 kinase (PI3K) signaling pathway is involved in lymphoid development. Defects in single components of this pathway prevent thymocytes from progressing beyond early T cell developmental stages. Protein kinase B (PKB) is the main effector of the PI3K pathway. Methodology/Principal Findings. To determine whether PKB mediates PI3K signaling in the thymus, we characterized PKB knockout thymi. Our results reveal a significant thymic hypocellularity in PKBa2/ 2 neonates and an accumulation of early thymocyte subsets in PKBa2/ 2 adult mice. Using thymic grafting and fetal liver cell transfer experiments, the latter finding was specifically attributed to the lack of PKBa within the lymphoid component of the thymus. Microarray analyses show that the absence of PKBa in early thymocyte subsets modifies the expression of genes known to be involved in pre-TCR signaling, in T cell activation, and in the transduction of interferon-mediated signals. Conclusions/Significance. This report highlights the specific requirements of PKBa for thymic development and opens up new prospects as to the mechanism downstream of PKBa in early thymocytes. ¨ Citation: Fa