Molecular controls of antigen receptor clustering and autoimmunity

Cellular organization of the cytoskeleton, assembly of intracellular signal ing complexes and movement of membrane receptors into supramolecular activa tion complexes (SMACs) are crucial prerequisites for lymphocyte activation and function. Full T-cell activation requires costimulatory signals in addi tion to antigen-mediated signals. Costimulatory signals facilitate T-cell a ctivation by inducing SMAC formation, resulting in sustained signal transdu ction, cell-cycle progression and cytokine production. The guanine nucleoti de exchange factor Vav1 and the Wiscott-Aldrich syndrome protein (WASP) reg ulate the actin cytoskeleton in T cells and also regulate SMAC formation. I n mice lacking the E3 ubiquitin ligase Cb1-b, the Vav-WASP signaling pathwa y is active in the absence of costimulation resulting in deregulated cytosk eletal reorganization, enhanced priming and expansion of autoreactive T cel ls, and the development of autoimmunity. This review discusses the role of Cb1-b, Vav and WASP in the regulation of SMAC formation and the implication s for the maintenance of tolerance end the development of autoimmunity.