Immunological synapse generates microenvironment for costimulation

Abstract

The two-signal hypothesis of T-cell activation predicts that signal one is transduced by the T-cell receptor (TCR) and enhanced by adhesion molecules, whereas signal two is generated by costimulatory molecules on the surface of the antigen-presenting cell (APC). The interaction of the costimulatory receptor CD28 with its ligands, CD80 and CD86, is topologically similar to that of many other adhesion molecules, such as CD2 and CD48/CD58, suggesting that CD28 plays a dual role as an adhesion and signalling molecule. The immunological synapse is characterized by a peripheral ring of adhesive LFA-1–ICAM-1 interactions surrounding a central cluster of TCR–peptide–MHC (pMHC) interactions, referred to as a central supramolecular activation cluster (cSMAC). The interaction of CD28 with CD80 is unusual as CD28 is colocalized with the engaged TCR. Engagement of CD28 promotes the cytoskeletal-dependent recruitment of cell-surface protein and lipid rafts rich in kinases and adaptor proteins that contribute to the formation of the immunological synapse. The distance spanned by the interaction of CD28 on T cells with its ligands CD80 or CD86 on APCs (∼15 nm) is similar to that spanned by TCR–pMHC interactions, so CD28 could generate the appropriate spacing for the TCR to interact efficiently with pMHC. However, a recent study indicates that CD28–CD80 interactions do not support adhesion and have little capacity for enhancing TCR–pMHC interactions, prompting a new view of the two-signal hypothesis.