Expression of Mad1 in T cells leads to reduced thymic cellularity and impaired mitogen-induced proliferation

To investigate Mad1 function in vivo, transgenic mice were:generated that e xpress a Mad1 transgene in T lineage cells under the control of the proxima l lck promoter. Thymus size in lck-Mad1 transgenic mice is drastically redu ced although representation of the various thymocyte sub populations appear s normal. To investigate more closely any effects of Mad1 expression on thy mocytes, we examined thymic selection using MHC class I-restricted H-Y-TCR transgenic mice. Mad1 expression in vivo reduces the efficiency of positive selection. Furthermore, thymocytes and splenic T cells from lck-Mad1 trans genic mice display a profound proliferative defect in response to activatio n with either PMA/lonomycin or immobilized anti-CD3/CD28 antibody. This pro liferative defect is not reversed by addition of exogenous IL-2 and is p53- independent. The growth inhibition caused by Mad1 is overcome by expression of active c-Myc.