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. 2020 Feb 27;13(3):100738. doi: 10.1016/j.tranon.2019.12.010

Figure 1.

Figure 1

Schematic representation of immune checkpoints and their signaling in T cells

A. PD-1: PD-1 ligation leads to tyrosine phosphorylation of the cytoplasmic tail of PD-1. This recruits SHP-2 to the cytoplasmic tail of PD-1. Activation of SHP-2 leads to dephosphorylation of TCR proximal kinases, causing inhibition of downstream signaling pathways [14], [15].

B. CTLA4: CTLA4 binds to B7 with a higher affinity than CD28, it then interacts with the tyrosine phosphatase SHP-2 and the serine/threonine phosphatase PP2A to inhibit T cells [16], [17].

C. LAG3: LAG3 binds MHC class II with greater affinity than does CD4. The signaling pathway for LAG3 has not been identified but the KIEELE motif has been shown to be essential for its inhibitory effects on CD4 T cells. Neither its effect on Tregs nor the intracellular proteins that bind it have yet to be identified [18].

D. VISTA: Research has shown that VISTA can function as both a receptor and a ligand, but another ligand, VSIG-3 has also been discovered. Once bound to VSIG-3, VISTA is able to inhibit T cell proliferation and cytokine production [19].

E. TIM-3: The binding of TIM-3 to its ligand Galectin-9 from tumor cells leads to phosphorylation of TIM 3 and the release of Bat-3. The release of Bat-3 allows for the interaction of TIM-3 with Fyn thereby mediating Th1 cell anergy [20].

Abbreviations: Bat3 = HLA (Human Leukocyte Antigen) B-associated transcript 3; CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; ITIM = immunoreceptor tyrosine-based inhibitory motif; ITSM = immunoreceptor tyrosine-based switch motif; LAG3 = lymphocyte-activation gene 3; MHC = major histocompatibility class; PI3K = phosphoinositide 3-kinase; P = phosphate; PD-1 = programmed cell death ligand-1; PP2A = protein phosphatase 2; SHP2 = Src homology phosphatase 2; TCR = T cell receptor; Th1 = Type 1 helper T cell; TIM-3= T cell immunoglobulin and mucin domain-3; Tregs = regulatory T cells; VISTA = V domain-containing immunoglobulin suppressor of T-cell activation; VSIG-3 = V-set and immunoglobulin domain containing 3.