1. Upon ligand engagement the cytoplasmic signalling motifs of co-inhibitory receptors such as ITIM or ITSM are phosphorylated and bind intracellular mediators such as the phosphatases SHP-1 and SHP-2, that then dephosphorylate key signalling molecules downstream of the T cell receptor. The suppression of transcription factors can also be classified under mechanism 1. Co-inhibitory receptors that use this mechanism are CTLA-4, PD-1, BTLA, TIM-3, LAIR-1and Siglecs.
2. Mechanism 2 is used by co-inhibitory receptors such as PD-1 and involves upregulating a program of genes that inhibit T cell function.
3. Mechanism 3 involves ectodomain competition. Here the co-inhibitory receptors (CTLA-4, BTLA, LAG-3, TIGIT and Siglecs) prevents optimal signal transduction at the cell membrane by sequestering counter receptors/ligands and/or preventing the formation of microclusters and lipid rafts which are necessary for immunological synapse formation and T cell activation.
