Full activation and differentiation of T cells requires a primary signal from T cell receptors (TCRs) upon interaction with an antigen-presenting cell (APC), and a second, distinct signal transmitted through ‘costimulatory’ receptors.
The receptor CD28 plays a predominant role in T cell costimulation. CD28-mediated signals augment many T cell functions, such as cytokine production and cell proliferation.
Modulation of these costimulatory signals has been applied in clinical trials by increasing tumor immunity and reducing autoimmune diseases. But the precise roles of molecules implicated in CD28-mediated costimulatory signals and their relationship with TCR signals require clarification.
An immunological synapse showing the central supramolecular activation cluster containing both T cell receptors (red) and PKC? (green).
Antigen-specific T cells ‘communicate’ with APCs through an ‘immunological synapse’, which forms at their interface and contains a central (c-) and a peripheral (p-) supramolecular activation cluster (SMAC).
At initial activation, TCRs form microclusters, which contain receptors, kinases, and adaptor proteins to induce activation signals at the interface between a T cell and an APC. These microclusters translocate to the center of the interface, resulting in cSMAC formation.
The role of microcluster translocation in T cell signaling has been unclear, and the concept that they function as signaling centers for T cell activation has raised questions as to how CD28-mediated costimulation is regulated.
Using sophisticated fluorescence microscopy techniques to study CD28-mediated costimulation at the molecular level, Saito and colleagues have found that the accumulation of microclusters at cSMAC is important for T cell costimulation. CD28 is initially recruited together with TCRs to microclusters. PKC?—a protein kinase acting downstream of CD28—is also recruited to microclusters by association with CD28, thereby resulting in the initial activation of T cells.
CD28 also plays a role in retaining PKC? at a spatially unique subregion of cSMAC, leading to sustained signals for T cell activation. “Thus, costimulation is mediated by the generation of a unique costimulatory compartment in the cSMAC via the dynamic regulation of microcluster translocation,” say the researchers.
Establishing the underlying mechanisms should lead to new treatments for autoimmune diseases, such as rheumatoid arthritis and psoriasis, as well as the prevention of graft versus host disease in transplantation, more effective vaccinations, and augmented anti-tumor immunity.