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. 2025 Sep 17;16:1647066. doi: 10.3389/fimmu.2025.1647066

Figure 2.

Illustration showing pathways involved in the inhibition of TCR signaling and activation. Four immune checkpoint receptors depict different interactions: LAG-3 with KIEELE and EP motifs, Tim-3 with phosphorylated Y256, TIGIT with IL-10 and IL-12 involvement, and VISTA with SH2 and SH3 domains. Arrows indicate activation of PI3K and inhibition of TCR signaling. APC, CD4, and other molecules are labeled.

Checkpoint schematic pathway. Mechanisms of LAG-3, Tim-3, TIGIT, and VISTA inhibitory pathways in T cells: (A) Upon ligand binding, LAG-3 inhibits early steps of the TCR pathway in a manner dependent on LAG-3’s cytoplasmic domain. The KIEELE motif is responsible for regulating downstream inhibitory signaling, while EP motifs interfere with T cell activation by blocking CD3/Lck interactions. (B) TIM-3 binds to Gal-9 and induces phosphorylation at Tyr256 and Tyr263, releasing Bat3, which regulates Lck tyrosine kinases, thereby inhibiting TCR signaling. (C) In T cells, TIGIT exhibits a variety of inhibitory mechanisms. 1) TIGIT directly lowers TCR expression and TCR signaling by binding to CD155 and delivering intracellular inhibitory signals. 2) TIGIT can outcompete CD226 in CD155 binding because it binds to CD155 with a significantly higher affinity than its co-stimulatory counterpart CD226; 3) TIGIT interferes with CD226 homodimerization to prevent CD226-mediated T cell activation. 4) TIGIT inhibits T cells indirectly by binding to CD155 on APCs, thereby increasing IL-10 production and decreasing IL-12 production. (D) VISTA can function as a receptor that preserves a tolerant or quiescent phenotype and as a ligand expressed by tumor cells that inhibits T-cell receptor-mediated activation by signaling through a putative receptor on T cells. VISTA can bind to PSGL-1 in acidic environments and to VSIG-3 in physiological environments, inhibiting T cell function and proliferation. This figure is adapted from (62, 63). Created in BioRender. Alsayb, M. (2025) https://BioRender.com/r2iqbmx.