Intraflagellar transport: a new player at the immune synapse

Abstract

The assembly and maintenance of primary cilia, which orchestrate signaling pathways centrally implicated in cell proliferation, differentiation and migration, are ensured by multimeric protein particles in a process known as intraflagellar transport (IFT). It has recently been demonstrated that a number of IFT components are expressed in hematopoietic cells, which have no cilia. Here, we summarize data for an unexpected role of IFT proteins in immune synapse assembly and intracellular membrane trafficking in T lymphocytes, and discuss the hypothesis that the immune synapse could represent the functional homolog of the primary cilium in these cells.

Figure 1

IFT in primary cilia and at the immune synapse. (a) Transport of cargo to primary cilia and back to the cell body is ensured by multimeric IFT particles in concert with the BBSome. Molecular motors (kinesin-2 for anterograde movement and dynein-1b for retrograde movement) assist the movement of particles along the axonemal microtubules. Ciliary proteins are prevented from entering the cilium by the ciliary necklace. Cytosolic proteins that are destined for the cilium are sorted by the IFT/BBSome particles at the base of the cilium based on specific targeting sequences, and are carried into the cilium as a complex with the particles. Ciliary membrane proteins are sorted by IFT20 at the Golgi and targeted to the periciliary membrane, from where they are carried to the ciliary membrane as a complex with an IFT particle. This process is assisted by the small GTPase Rab8. (b) When a T cell encounters an antigen-specific APC, the TCR/CD3 complex clusters in the central area of the immune synapse. The integrin LFA-1, which accumulates as a ring peripherally to the TCR, interacts with newly polymerized actin filaments through the adaptor talin, which results in stabilization of the immune synapse. One of the principal mechanisms of TCR clustering at the immune synapse is through polarized delivery of receptor complexes localized in recycling endosomes. Assembly of a stable immune synapse requires the translocation of the centriole close to the membrane patch at the immune synapse. In quiescent cells, IFT20 colocalizes with the centriole and Golgi, as well as with post-Golgi compartments, including recycling endosomes. Following TCR engagement, IFT20 interacts with the TCR and assembles in a complex with IFT57 and IFT88. This IFT complex promotes polarized recycling of the TCR to the immune synapse.