Figure 2.

Interactions between antigen presenting cell and T cell. The major histocompatibility complex-peptide (pMHC) complex on APC or tumor cell recognizes and binds TCRs from T cells, while CD80/CD86 binds CD28 and fully activates TCR-CD28 signaling, promoting T cell activation, proliferation, and triggering the expression of associated transcription factors such as nuclear factor of activated T cells (NF-AT), activator protein 1 (AP-1) and nuclear factor-κB (NF-κB). PD1 could bind with PD-L1 expressed by APC or tumor cell and cause dephosphorylation of Zap70 and Ras by recruiting phosphatases, such as SHP2, to the tyrosine-based immunoreceptor switch motif (ITSM) in the intercellular domain of PD1, inducing inhibition of the relevant pathway. Besides, PD1 increases the expression of transcription factors such as BATF (basic leucine zipper transcription factor, ATF-like) to inhibit T cell function. LAG-3 contains four IgSF domains, each of which contains a glycosylation site. There’re several ligands of LAG-3 like LSECtin expressed on the surface of APC or tumor cells, and FGL-1 secreted by tumor cells. FGL-1 binds to D1 and D2 domain of LAG-3 and LSECtin binds to D2 domain of LAG-3. TIGIT is composed of an extracellular Ig variable (IgV) domain, a type 1 transmembrane domain, and a cytoplasmic tail with two inhibitory motifs: an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an Ig tail-tyrosine (ITT)-like motif. Binding to its ligand phosphorylates the cytoplasmic tail of TIGIT which binds to cytosolic adaptor growth factor receptor-bound protein 2 (Grb2), recruiting SH2-containing inositol phosphate-1 (SHIP-1) which inhibits PI3K and MAPK signaling cascades.