Functional anatomy of T cell activation and synapse formation

Abstract

T cell activation and function require a structured engagement of antigen-presenting cells. These cell contacts are characterized by two distinct dynamics in vivo: transient contacts resulting from promigratory junctions called immunological kinapses or prolonged contacts from stable junctions called immunological synapses. Kinapses operate in the steady state to allow referencing to self-peptide-MHC (pMHC) and searching for pathogen-derived pMHC. Synapses are induced by T cell receptor (TCR) interactions with agonist pMHC under specific conditions and correlate with robust immune responses that generate effector and memory T cells. High-resolution imaging has revealed that the synapse is highly coordinated, integrating cell adhesion, TCR recognition of pMHC complexes, and an array of activating and inhibitory ligands to promote or prevent T cell signaling. In this review, we examine the molecular components, geometry, and timing underlying kinapses and synapses. We integrate recent molecular and physiological data to provide a synthesis and suggest ways forward.

Figure 1

Receptor-ligand kinetics in solution versus membranes. In theory, dissociation constants (Kd) for bound ligands in solution are calculated based on dissociation occurring in 3-D space, with six degrees of freedom. However, some of these receptor-ligand interactions occur when two opposed cell membranes (or in this case, cell membrane and artificial lipid bilayer) are interacting. Under these circumstances, ligands are confined to 2-D translation and 1-D rotation, which may stabilize and prolong these interactions. Also, rebinding by cis-receptors (such as clustered TCR) can further trap ligands and generate longer binding than would be predicted in solution.

Figure 2

Spatiotemporal map of synapse formation. Side and en face views of the T cell as it engages an APC. The migrating cell has a polarized cell body with actin polymerization at the leading edge and myosin contraction at the uropod. The membrane topology in the migrating cell is poorly understood. The early/immature synapse has symmetrical actin polymerization radiating outward from the center along the perimeter of the contact surface and cytoskeletal contractions through myosin radially inward to the center. The early synapse only contains microclusters, and after a few minutes these accumulate and form the cSMAC.