ABSTRACT
It has been recognized since the 1970s that T cells require at least two signals for full activation leading to maximum proliferation and cytokine production.1-3 The first signal is provided by the clonotypic cell surface T-cell receptor (TCR) when it engages a specific major histocompatibility complex (MHC) molecule-peptide complex on an antigen-presenting cell (APC). The second activating signal(s) is provided by costimulatory ligands expressed on the T-cell surface that engage cognate receptors on the surface of APCs. The initiation and progression of the immune response is controlled by spatial and temporal regulation of the expression of costimulatory and coinhibitory ligands and their receptors. In general, T cells that receive only the first signal through the TCR in the absence of a second costimulatory signal become anergic and non-responsive. However, in certain circumstances, T cells may become activated after receiving a potent agonist signal via the TCR. In addition to receiving costimulatory signals, T cells may also receive coinhibitory signals, which results in the attenuation of costimulatory signals and interruption of T-cell activation and cytokine secretion. The expression pattern of costimulatory and coinhibitory ligands and their receptors is regulated over the course of the immune response, ensuring an optimal balance of stimulatory and inhibitory signals to enable effective clearance of antigen or pathogen and a diminution of the response once the antigen or
pathogen is cleared. Thus, T-cell costimulation and coinhibitory pathways have evolved to facilitate initiation of appropriate immune responses, which are subsequently regulated to avoid uncontrolled T-cell activation and the attendant potential risk of autoimmunity.
