Two families of cell surface receptors are integral to the control of lymphocyte survival and programmed cell death (apoptosis): the tumor necrosis factor receptor family and the CD28/CTLA4 family. Tumor necrosis factor receptor family members bind a related collection of ligands (the tumor necrosis factor family) that can either induce or inhibit cell death. Two of the tumor necrosis factor receptor family members, tumor necrosis factor receptor 1 and Fas, have been implicated in the termination of immune responses through their ability to induce apoptosis. A number of cytoplasmic proteins implicated in signal generation by these receptors recently have been identified. These proteins fall into several related classes sharing intriguing structural motifs. The CD28 and CTLA4 molecules share at least two extracellular ligands and signaling through the two receptors appears to determine the apoptotic sensitivity of activated T cells. The effects of CD28 and CTLA4 on cell survival are dependent on T-cell antigen receptor engagement, providing a potent mechanism for clonally specific T-cell expansion or deletion. The study of the apoptotic pathways in lymphocytes has led to a better understanding of the mechanisms of autoimmune disease and serves as a model system for the study of the regulation of cell survival and tissue homeostasis.
