MTOC translocation modulates IS formation and controls sustained T cell signaling

The translocation of the microtubule-organizing center (MTOC) toward the nascent immune synapse (IS) is an early step in lymphocyte activation initiated by T cell receptor (TCR) signaling. The molecular mechanisms that control the physical movement of the lymphocyte MTOC remain largely unknown. We have studied the role of the dynein-dynactin complex, a microtubule-based molecular motor, in the process of T cell activation during T cell antigen-presenting cell cognate immune interactions. Impairment of dynein-dynactin complex activity, either by overexpressing the p50-dynamitin component of dynactin to disrupt the complex or by knocking down dynein heavy chain expression to prevent its formation, inhibited MTOC translocation after TCR antigen priming. This resulted in a strong reduction in the phosphorylation of molecules such as zeta chain-associated protein kinase 70 (ZAP70), linker of activated T cells (LAT), and Vav1; prevented the supply of molecules to the IS from intracellular pools, resulting in a disorganized and dysfunctional IS architecture; and impaired interleukin-2 production. Together, these data reveal MTOC translocation as an important mechanism underlying IS formation and sustained T cell signaling.This study was supported by the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Spain (Red Temática de Investigación en Enfermedades Cardiovasculares grant RD06/0021/2006 and postdoctoral fellowship to N.B. Martín-Cófreces), Ministerio de Educación y Ciencia of Spain (grant BFU200508435/BMC and Formación Profesorado Universitario fellowship to J. Robles-Valero), Juan March Foundation (Ayuda a la Investigación Básica 2002) and grant INSINET0159/2006 from Comunidad de Madrid.S