Dynamic regulation of T-cell costimulation through TCR-CD28 microclusters

T-cell activation requires contact between T cells and antigen-presenting cells (APCs) to bring T-cell receptors (TCRs) and major histocompatibility complex peptide (MHCp) together to the same complex. These complexes rearrange to form a concentric circular structure, the immunological synapse (IS). After the discovery of the IS, dynamic imaging technologies have revealed the details of the IS and provided important insights for T-cell activation. We have redefined a minimal unit of T-cell activation, the 'TCR microcluster', which recognizes MHCp, triggers an assembly of assorted molecules downstream of the TCR, and induces effective signaling from TCRs. The relationship between TCR signaling and costimulatory signaling was analyzed in terms of the TCR microcluster. CD28, the most valuable costimulatory receptor, forms TCR-CD28 microclusters in cooperation with TCRs, associates with protein kinase C theta, and effectively induces initial T-cell activation. After mature IS formation, CD28 microclusters accumulate at a particular subregion of the IS, where they continuously assemble with the kinases and not TCRs, and generate sustained T-cell signaling. We propose here a 'TCR-CD28 microcluster' model in which TCR and costimulatory microclusters are spatiotemporally formed at the IS and exhibit fine-tuning of T-cell responses by assembling with specific players downstream of the TCR and CD28.