LYMPHOCYTE-ACTIVATION IN HEALTH AND DISEASE

Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimula ting both proliferation and apoptosis. The antigen/major histocompatib ility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmittin g information down various signaling cassettes (e.g., the IP3/Ca2+, DA G/PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 ma y exert its costimulatory action by facilitating the assembly of an ef fective scaffold of signaling elements within the TCR complex. The abs ence 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 cy tosolic 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 JA K/STAT and the sphingomyelinase/ceramide pathways) to mediate their ef fects on proliferation and apoptosis, respectively. Information concer ning these signaling systems is beginning to provide therapeutic strat egies to manipulate the immune system to overcome human immunodeficien cy virus (HIV) infection, autoimmune diseases, and graft rejection.