Immunological memory provides us with a long-lived immunity to reinfection by pathogens. The activation of antigen-specific cells during the primary response leads to the generation of effector cells, some of which survive indefinitely as a long-lived population of cells, referred to as memory cells. Upon reinfection, the response is more effective due to the an increased number of antigen-specific lymphocytes available, due to the increased responsiveness of the memory cells, and due to the greater flexibility of memory cell recirculation. However, these properties of the memory cell pool which provide immunity could pose a problem in the maintenance of peripheral tolerance. The focus of this proposal is to study a unique mechanism of peripheral tolerance found only in memory and not naive CD4 T cells and determine if this mechanism leading to memory CD4 T cell unresponsiveness is important in peripheral tolerance. Our studies have shown that CD4 ligation by MHC class II upon memory but not naive CD4 T cell activation leads to unresponsiveness. The induction of memory CD4 T cell unresponsiveness is due to CTLA4/B7 interaction which occurs upon TCR signalling, suggesting that CTLA4 plays an early role in determining memory CD4 T cell responsiveness. In this proposal, we will 1) determine the role of CTLA4 signalling in memory CD4 T cell responses and 2) analyze how CD4 ligation regulates CTLA4 function/expression. Given that CD4 ligation by antibody and HIV glycoprotein GP120 leads to unresponsiveness to TCR signalling, understanding the role of CD4 ligation in CTLA4 function in memory cells will provide an understanding of a novel mechanism for downregulating recall responses that accompanies HIV-1 infections.