Differential signaling by lymphocyte antigen receptors

Studies performed during the past several years make plain that ligand occupancy of antigen receptors need not necessarily provoke identical responses in all instances. For example, ligation of antigen receptors may stimulate a proliferative response, induce a state of unresponsiveness to subsequent stimulation (anergy), or induce apoptosis. How does a single type of transmembrane receptor induce these very heterogeneous cellular responses? In the following pages, we outline evidence supporting the view that the nature of the ligand/receptor interaction directs the physical recruitment of signaling pathways differentially inside the lymphocyte and hence defines the nature of the subsequent immune response. We begin by providing a functional categorization of antigen receptor components, considering the ways in which these components interact with the known set of signal transduction pathways, and then review the evidence suggesting that differential signaling through the TCR is achieved by qualitative differences in the effector pathways recruited by TCR, perhaps reflecting the time required to bring complicated signal transduction elements into proximity within the cell. The time-constant of the interaction between antigen and receptor in this way determines, at least in part, the nature of the resulting response. Finally, although our review focuses substantially on T cell receptor signaling, we have included a less detailed description of B cell receptor signaling as well, simply to emphasize the parallels that exist in these two closely related systems.