Abstract
Interactions among immune cells are essential for the development of adaptive immune responses. The immunological synapse (IS) provides a specialized platform for integration of signals and intercellular communication between T lymphocytes and antigen presenting cells (APCs). In the T cell the reorganization of surface molecules at the synaptic interface is initiated by T cell receptor binding to a cognate peptide-major histocompatibility complex on the APC surface and is accompanied by a polarized remodelling of the cytoskeleton and centrosome reorientation to a subsynaptic position. Although there is a general agreement on polarizing signals and mechanisms driving centrosome reorientation during IS assembly, the primary events that prepare for centrosome repositioning remain largely unexplored. It has been recently shown that in resting lymphocytes a local polymerization of filamentous actin (F-actin) at the centrosome contributes to anchoring this organelle to the nucleus. During early stages of IS formation centrosomal F-actin undergoes depletion, allowing for centrosome detachment from the nucleus and its polarization towards the synaptic membrane. We recently demonstrated that in CD4+ T cells the reduction in centrosomal F-actin relies on the activity of a centrosome-associated proteasome and implicated the ciliopathy-related Bardet-Biedl syndrome 1 protein in the dynein-dependent recruitment of the proteasome 19S regulatory subunit to the centrosome. In this short review we will feature our recent findings that collectively provide a new function for BBS proteins and the proteasome in actin dynamics, centrosome polarization and T cell activation.
Highlights
The immunological synapse (IS) is a specialized interface formed by T lymphocytes with antigen presenting cells (APCs) bearing a cognate peptide-major histocompatibility complex that allows for information exchange and execution of effector functions [1, 2]
Post-endocytic T cell receptors (TCRs) are directed to multivesicular bodies (MVBs) and incorporated in intraluminal vesicles (ILVs), which are released into the synaptic cleft as exosomes and taken up by APCs [20]
Multiple signaling pathways initiated at the IS by the TCR, the integrin LFA-1 and the co-stimulatory receptor CD28 coordinate the activation of several actin-regulatory proteins that promote Factin polymerization, feeding back for optimal TCR signaling, integrin activation and T cell spreading over the APC [33, 34]
Summary
The immunological synapse (IS) is a specialized interface formed by T lymphocytes with antigen presenting cells (APCs) bearing a cognate peptide-major histocompatibility complex (pMHC) that allows for information exchange and execution of effector functions [1, 2]. Multiple signaling pathways initiated at the IS by the TCR, the integrin LFA-1 and the co-stimulatory receptor CD28 coordinate the activation of several actin-regulatory proteins that promote Factin polymerization, feeding back for optimal TCR signaling, integrin activation and T cell spreading over the APC [33, 34] Both disruption of synaptic actin networks and depletion of F-actin nucleators (e.g. the formins diaphanous 1 and formin-like-1) result in impaired centrosome mobilization and in defective TCR signaling, suggesting an indirect role of actin in centrosome repositioning. F-actin polymerizes at recycling endosomes through the assistance of the F-actin regulator Wiskott-Aldrich Syndrome protein and SCAR Homology (WASH) and its partner FAM21 to help membrane scission of nascent vesicles carrying recycling cargo, including the TCR, LFA-1, CD28 and the glucose transporter GLUT-1 These receptors exploit the recycling pathway to accumulate at the IS, where they participate in mature IS formation and maintenance, as well as in the metabolic reprogramming of activated T cells [38]. Actin plays a dual role during secretion depending on the maturation stage of the lytic synapse: at immature synapses a dense actin cortex blocks secretion, while in mature, actin-hypodense synapses nanoscale actin filament dynamics fine-tunes regulated lytic granule exocytosis [45]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
