T-cell co-stimulatory and co-inhibitory receptors (Immune Checkpoints)

T-cell co-stimulatory and co-inhibitory receptors, collectively known as immune checkpoints, are a diverse group of cell-surface molecules that regulate the magnitude and duration of immune responses. The activation of a T-cell requires two signals: the primary signal from the T-cell receptor (TCR) recognizing an antigen and a secondary co-stimulatory signal, most notably provided by the interaction between CD28 and its ligands, CD80 (B7-1) and CD86 (B7-2) (Sharpe & Freeman, 2002, Nature Reviews Immunology). Conversely, co-inhibitory receptors such as CTLA-4 and PD-1 serve as negative regulators that dampen T-cell activity to maintain self-tolerance and prevent tissue damage (Pardoll, 2012, Nature Reviews Cancer). In oncology, many tumors exploit these inhibitory pathways to evade the immune system, leading to the clinical success of checkpoint inhibitors like Pembrolizumab and Ipilimumab that block these "brakes" to restore anti-tumor immunity. In the context of autoimmunity and transplantation, the pathway is targeted in the opposite direction; for example, Abatacept is a fusion protein that blocks the CD28/B7 co-stimulatory signal to reduce pathological T-cell activation (Chen & Flies, 2013, Nature Reviews Immunology). These receptors are also being investigated in chronic infections where T-cell exhaustion is a factor, highlighting their broad therapeutic potential across multiple disease areas.

Other names

Immune checkpointsCo-signaling moleculesCD28 familyB7-CD28 superfamilyCostimulatory moleculesT-cell co-receptors

Therapeutic strategies involve either blocking inhibitory receptors (checkpoint inhibitors) to enhance anti-tumor immunity or blocking co-stimulatory pathways (co-stimulation blockers) to suppress unwanted immune responses in autoimmunity and transplantation.