Mst1 Regulation Of Thymocytes To Move Out And Function In The Central Immune Tolerance

The Mst1 kinase was recently identified as playing an essential role in the promotion of lymphocyte polarization and adhesion stimulated by chemokines and TCR signaling. However, the physiological relevance of the Mst1 pathway in thymocyte development is not completely understood. In this study, we analyzed the effect of Mst1 disruption on thymocyte development and migration. Mst1-deficient (Mst1-/-) mice displayed an accumulation of mature thymocytes in the thymus, a dramatic reduction of lymphocytes in blood and peripheral lymphoid tissues, and a decrease of homing ability to peripheral lymph nodes. Mst1-/-thymocytes were impaired in chemotactic response to chemokines, such as CCL19, but not to sphingosine-1-phosphate. Further analyses of Mst1-/- mice revealed a severe impairment in the egress of mature T cells from the thymus. T lineage-specific knockout of the Mst1 gene demonstrates a cell-intrinsic role for Mst1 in regulating T cell development.Mst1-deficient(Mst11-/-) mice also spontaneously and progressively develop autoimmuno-disease syndromes, including lymphocyte infiltrations in lachrymal and salivary glands and production of anti-nuclear antibody. Mice with T lineage-specific knockout of the Mst1 gene also display similar but delayed symptoms, indicating a dominant role of Mst1-/- T cells in the disease development. Further studies showed that the process of negative selection was impaired in Mst1-/-thymus, suggesting that impaired central tolerance contributes to the development of autoimmune diseases.Our study indicates that Mst1 is crucial in controlling lymphocyte chemotaxis and thymocyte emigration. This study also provides a novel animal model for studying pathogenesis of autoimmune diseases, and may shed light on future clinical prevention, diagnosis, drug discovery and therapy.