Molecular controls of antigen receptor clustering and autoimmunity

Cellular organization of the cytoskeleton, assembly of intracellular signaling complexes and movement of membrane receptors into supramolecular activation complexes (SMACs) are crucial prerequisites for lymphocyte activation and function. Full T-cell activation requires costimulatory signals in addition to antigen-mediated signals. Costimulatory signals facilitate T-cell activation by inducing SMAC formation, resulting in sustained signal transduction, cell-cycle progression and cytokine production. The guanine nucleotide exchange factor Vav1 and the Wiscott-Aldrich syndrome protein (WASP) regulate the actin cytoskeleton in T cells and also regulate SMAC formation. In mice lacking the E3 ubiquitin ligase Cbl-b, the Vav-WASP signaling pathway is active in the absence of costimulation resulting in deregulated cytoskeletal reorganization, enhanced priming and expansion of autoreactive T cells, and the development of autoimmunity. This review discusses the role of Cbl-b, Vav and WASP in the regulation of SMAC formation and the implications for the maintenance of tolerance and the development of autoimmunity.