The regulation of actin remodeling during T-cell-APC conjugate formation

The T-cell cytoskeleton is intimately involved in determining the efficiency and fidelity of the immune response. During T-cell interactions with antigen-presenting cells (APCs), dynamic remodeling of the actin cytoskeleton is particularly important for stabilizing long-lived integrin-dependent adhesive interactions. In addition, actin remodeling is important for facilitating the sustained signaling required for full T-cell activation. Although the relationship between T-cell signaling and cytoskeletal remodeling is complex, new molecular genetic tools are making it possible to investigate individual molecular interactions in the context of bona fide conjugate formation. We describe here the progress from our laboratory toward defining the pathways required for actin remodeling during conjugate formation. Our studies show that engagement of T-cell receptor (TCR) and leukocyte functional antigen-1 (LFA-1) leads to distinct effects on the remodeling of individual cytoskeletal elements. Downstream of TCR, we find that p56Lck (Lck) plays a critical role in integrin-dependent adhesion independent of its ability to activate zeta-associated protein of 70 kDa (ZAP-70). TCR engagement also results in the assembly of a signaling complex that facilitates the activation of Wiskott-Aldrich syndrome protein (WASP) by colocalization with Cdc42-GTP. These events, together with other parallel actin regulatory pathways, induce localized actin polymerization at the site of APC binding.