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Review
. 2019 Jul 29;8(8):789.
doi: 10.3390/cells8080789.

A Ciliary View of the Immunological Synapse

Chiara Cassioli  1 , Cosima T Baldari  2
Affiliations
Review

A Ciliary View of the Immunological Synapse

Chiara Cassioli et al. Cells. .

Abstract

The primary cilium has gone from being a vestigial organelle to a crucial signaling hub of growing interest given the association between a group of human disorders, collectively known as ciliopathies, and defects in its structure or function. In recent years many ciliogenesis proteins have been observed at extraciliary sites in cells and likely perform cilium-independent functions ranging from regulation of the cytoskeleton to vesicular trafficking. Perhaps the most striking example is the non-ciliated T lymphocyte, in which components of the ciliary machinery are repurposed for the assembly and function of the immunological synapse even in the absence of a primary cilium. Furthermore, the specialization traits described at the immunological synapse are similar to those seen in the primary cilium. Here, we review common regulators and features shared by the immunological synapse and the primary cilium that document the remarkable homology between these structures.

Keywords: T lymphocytes; ciliary proteins; extraciliary functions; immunological synapse; primary cilium.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Schematic representation of critical steps in immunological synapse (IS) assembly and ciliogenesis. Both IS assembly and ciliogenesis are inducible processes that are initiated in response to external stimuli or triggering events. The encounter of an antigen presenting cell (APC) bearing a cognate peptide-loaded major histocompatibility complex (pMHC) initiates the formation of a stable IS in the T cell (a). At variance, ciliogenesis is activated in vitro by a variety of stressful conditions (e.g., serum and nutrient starvation, ultraviolet light radiation), which generally inhibit cell division (b). In the T cell the centrosome moves toward the synapse as a consequence of early T cell receptor (TCR) signaling events (a) and, at this location, sets the stage for polarized vesicular trafficking. Cilium assembly crucially depends on centrosome-to-basal-body conversion that consists in the polarization and subsequent docking of the mother centriole to the plasma membrane, where it nucleates the ciliary axoneme. During ciliogenesis, centrosome repositioning is associated with the Rab11-Rab8 dependent generation and expansion of a cap vesicle above the mother centriole (b). At the IS newly polymerized actin filaments contribute to the initial clustering of TCRs in the central supramolecular activation clusters (cSMAC). Following polarization of the centrosome, actin retracts to the distal SMAC (dSMAC) to form a ring, which surrounds the peripheral SMAC (pSMAC) enriched in LFA-1 (a). A redistribution of actin in contractile bundles at the ventral side and a cortical network at the dorsal side helps to break cell symmetry and promotes centrosome migration during ciliogenesis (b). In both structures the docking phase of the centrosome is concomitant with a local clearance of cortical actin.
Figure 2
Figure 2
Vesicular trafficking at the primary cilium and the IS. The signaling function of both the primary cilium and the IS relies on the delivery of receptors and signaling mediators to a specialized membrane patch. (a) In ciliated cells membrane-associated proteins are sorted at the TGN into vesicles that reach the base of the cilium either directly (direct trafficking pathway, in blue) or through recycling endosomes (recycling trafficking pathway, in red), and then dock to the periciliary membrane. Alternatively, vesicles carrying ciliary receptors fuse with the plasma membrane and receptors are then transferred to the ciliary membrane by lateral diffusion (later trafficking pathway, in blue). A specific pathway for N-myristoylated proteins involves Unc119-RP2-ARL3 (Unc-119 dependent trafficking pathway, in purple). Within the cilium, the bidirectional transport of proteins depends on the IFT-A and IFT-B subcomplexes that move along the axoneme in association with molecular motors. The BBSome stabilizes the interaction between IFT-A and IFT-B during anterograde transport, while it helps the recruitment of receptors by IFT-B allowing for their retrograde transport. Activated receptors that are not retrieved back to the cell body undergo ectocytosis from the ciliary tip. (b) Polarized recycling together with passive lateral diffusion and active-mediating movement of TCR-microclusters (TCR-MCs) drive the accumulation of TCRs and signaling molecules at the IS. This process involves the microtubule-dependent polarized transport of intracellular pools associated with recycling endosomes. The translocation of the centrosome and associated Golgi apparatus as well as of the recycling compartment to a site just beneath the IS is a crucial event for the establishment of polarized vesicular trafficking. In addition to general recycling regulators (i.e., Rab4, Rab5 and Rab11), different Rab GTPases, IFT proteins, SNAREs and adapters are combined to specifically control the polarized transport of the TCR, LAT and Lck to the IS. From the dissection of these pathways, several proteins have emerged as shared participants in ciliogenesis and IS, suggesting that the non-ciliated T cells co-opt components of the ciliary machinery to control polarized recycling. Regulators, the function of which has not been mapped to a specific step in the pathways yet, are not depicted in the figure.
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