Antigen-induced release and retroviral subversion of TCR-enriched microvesicles at the CD4+ T cell immunological synapse (58.5)

Abstract

Abstract The immunological synapse (IS) is a specialized junction that forms between T cells and antigen presenting cells, which is critical for effective T cell antigen recognition and effector functions. Its spatiotemporal evolution results in laterally segregated supramolecular domains composed of a peripheral adhesive ring of the β2 integrin LFA-1 and its ligand ICAM-1, and centrally accumulated T cell receptors (TCR). The molecular and cell biological basis for supramolecular domain organization at the IS remains unclear. Here we show, using novel correlative optical-electron microscopy methods in conjunction with electron tomography, that centrally accumulated TCR is located on the surface of microvesicles that are shed at the IS center. The ESCRT I member TSG101 sorts TCR into microvesicles. TCR-enriched microvesicles (TEMs) are transferred from T cell to B cell during cognate antigen recognition, and B cells initiate intracellular signals in response to TEMs, suggesting their involvement in intercellular communication between immune cells. Expression of the HIV GAG structural polyprotein in human CD4+ T cells, displaces TCR from microvesicles at the IS, resulting in the release of GAG-containing virus-like particles. These findings provide an ultrastructural basis for supramolecular domain organization at the IS, and identify an ESCRT-dependent mechanism for production of stimulatory TEMs, which may be co-opted during infection for the release of enveloped viruses.