T-cell receptor-peptide-Major Histocompatibility Complex and costimulatory molecules (TCR-pMHC-costim complex)

The T-cell receptor-peptide-Major Histocompatibility Complex (TCR-pMHC) and costimulatory molecules collectively form the immunological synapse, a specialized signaling interface between a T lymphocyte and an antigen-presenting cell (APC) or target cell [1, 2, 3]. T-cell activation follows a canonical multi-signal model where 'Signal 1' is established by the specific binding of the TCR to a peptide fragment presented by MHC molecules, providing the necessary specificity for immune recognition [4, 11, 15]. 'Signal 2' is provided by a diverse set of costimulatory or coinhibitory molecules (such as CD28, CD80/86, PD-1, and CTLA-4) that modulate the magnitude, duration, and nature of the T-cell response [4, 8, 9]. This complex system is the primary target of modern immunotherapy; drugs such as checkpoint inhibitors release the 'brakes' on the immune system by blocking inhibitory signals, while TCR-based therapies and bispecific engagers aim to stabilize or engineer the synapse to enhance the destruction of cancer cells or infected cells [5, 10, 13]. Conversely, suppressing these signals is a key strategy for treating autoimmune diseases and preventing transplant rejection [4, 12].

Other names

Immunological synapseImmune synapseSupramolecular activation cluster (SMAC)T-cell receptor-pMHC-costimulatory synapseSignal 1 and Signal 2 complex

TCR engagement, Immune checkpoint blockade, Costimulation modulation, T-cell redirection, Agonism of costimulatory receptors