RT Journal Article ID 41b8dae05621b643 A1 Berridge, Michael J. T1 Lymphocyte Activation in Health and Disease JF Critical Reviews™ in Immunology JO CRI YR 2017 FD 2018-03-22 VO 37 IS 2-6 SP 463 OP 487 K1 proliferation K1 apoptosis K1 inositol trisphosphate K1 calcium K1 protein kinase C K1 ras K1 CD28 K1 gene transcription K1 IL-2 K1 Fas K1 ceramide AB Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimulating both proliferation and apoptosis. The antigen/major histocompatibility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmitting information down various signaling cassettes (e.g., the IP3/Ca2+, DAG/ PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 may exert its costimulatory action by facilitating the assembly of an effective scaffold of signaling elements within the TCR complex. The absence of costimulation through CD28 seems to result in the assembly of a defective scaffold that reverses slowly and may thus account for the state of unresponsiveness responsible for peripheral T-cell tolerance. The signaling cassettes activated by the TCR and CD28 then engage cytosolic factors that transmit information into the nucleus to activate the genes that code for the IL-2 and Fas signaling pathways. The IL-2 and Fas receptors employ additional signaling cassettes (e.g., the JAK/STAT and the sphingomyelinase/ceramide pathways) to mediate their effects on proliferation and apoptosis, respectively. Information concerning these signaling systems is beginning to provide therapeutic strategies to manipulate the immune system to overcome human immunodeficiency virus (HIV) infection, autoimmune diseases, and graft rejection. PB Begell House LK https://www.dl.begellhouse.com/journals/2ff21abf44b19838,069604365dd5c794,41b8dae05621b643.html