We have identified cloned, alloreactive cytotoxic lymphocytes with multiple, genetically defined antigen specificities. The hierarchy of antigenic specificities for lysis is opposite the hierarchy of antigenic specificities for growth stimulation. This dichotomy of function (lysis and growth) associated with genetically defined specificities has suggested a model of T-cell diversity and differentiation based on the expression of alloreactive receptors coupled to assymetric units that determine the functional response to antigen-receptor interaction. We will test this model by characterization of other multispecificity clones isolated from populations of lymphocytes at various steps along the differentiation pathway. A resolution of these issues will permit a better understanding of the normal processes used by mammalian organisms in learning self from nonself and thus restricting the use of the destructive immune arsenal to appropriate pathogens. Also, we will use the dichotomy between proliferative and lytic stimuli to begin to probe the series of events between the interaction of antigen and the CTL receptor and the subsequent cellular response. In addition, we have found that we can modulate the lytic activity against tumors with some clones of lymphocytes. We will explore this modulation of lytic activity in an effort to understand the various extracellular signals and intracellular events involved in moving a cell from a resting, nonfunctional state to a fully functional lytic state. Further, we will examine functional markers to carefully define the various intermediate steps along the way between the nonfunctional and fully functional states. By providing a detailed description of the important points in the normal induction process, these experiments will establish the framework for future studies on the events regulating lytic function.
NIH ExPorter
NIH ExPorter