Figure 1.
Downstream signaling pathways of immune IRs following ligand engagement. (i) CTLA-4 competes with CD28 for CD80/CD86, limiting costimulation and antigen presentation. Its cytoplasmic tail recruits PP2A to inhibit AKT and SHP-2 to suppress ZAP70 and ERK signaling, while also mediating ligand removal via trans-endocytosis and trogocytosis. CTLA-4 on Tregs further enhances suppressive function by increasing IL-10 and TGF-β secretion. (ii) PD-1, through its ITIM and ITSM motifs, recruits SHP-1/2 upon PD-L1/PD-L2 engagement, leading to PI3K inhibition, CD28 dephosphorylation, and suppression of TCR signaling. (iii) LAG3 binds MHCII and associates with the TCR/CD3 complex, where its cytoplasmic motifs (FSALE, KIEELE, EP) disrupt Lck association from the coreceptors (CD4 and CD8) and the CD3ε-Lck interaction, thereby reducing ZAP70 activation. (iv) TIM-3 impairs antigen presentation and cytokine production in APCs. Its cytoplasmic tail is phosphorylated at Y256 and Y263 to recruit SH2-domain adaptors, while Bat3 binding prevents TIM-3–mediated exhaustion. (v) TIGIT binding to CD155 delivers inhibitory signals through ITIM and ITT-like motifs that recruit SHIP1 and GRB2, blocking PI3K, MAPK, and NF-κB pathways. CD155 engagement on APCs promotes a tolerogenic phenotype with elevated IL-10, while enhancing Treg activity and suppressing Teffs. The figure was created with BioRender. Refer to the image caption for details. The diagram illustrates inhibitory receptor interactions between antigen-presenting cells (APCs) and T cells and their downstream signaling effects. Ligands of inhibitory receptors regulate immune responses by influencing antigen presentation, inducing tolerogenic signals, and modulating cytokine production. The figure highlights several receptor-ligand pathways including CD80/CD86–CTLA4, PDL1/PDL2–PD1, MHCII–LAG3, Gal9–TIM3, and CD155–TIGIT. These interactions activate intracellular signaling molecules such as PI3K, SHP1/SHP2, PP2A, and LCK that regulate T cell signaling pathways. As a result, transcriptional changes occur that influence activation and function of APC s and T cells. Overall, these pathways regulate cytokine production, growth factor signaling, and immune cell proliferation.

Downstream signaling pathways of immune IRs following ligand engagement. (i) CTLA-4 competes with CD28 for CD80/CD86, limiting costimulation and antigen presentation. Its cytoplasmic tail recruits PP2A to inhibit AKT and SHP-2 to suppress ZAP70 and ERK signaling, while also mediating ligand removal via trans-endocytosis and trogocytosis. CTLA-4 on Tregs further enhances suppressive function by increasing IL-10 and TGF-β secretion. (ii) PD-1, through its ITIM and ITSM motifs, recruits SHP-1/2 upon PD-L1/PD-L2 engagement, leading to PI3K inhibition, CD28 dephosphorylation, and suppression of TCR signaling. (iii) LAG3 binds MHCII and associates with the TCR/CD3 complex, where its cytoplasmic motifs (FSALE, KIEELE, EP) disrupt Lck association from the coreceptors (CD4 and CD8) and the CD3ε-Lck interaction, thereby reducing ZAP70 activation. (iv) TIM-3 impairs antigen presentation and cytokine production in APCs. Its cytoplasmic tail is phosphorylated at Y256 and Y263 to recruit SH2-domain adaptors, while Bat3 binding prevents TIM-3–mediated exhaustion. (v) TIGIT binding to CD155 delivers inhibitory signals through ITIM and ITT-like motifs that recruit SHIP1 and GRB2, blocking PI3K, MAPK, and NF-κB pathways. CD155 engagement on APCs promotes a tolerogenic phenotype with elevated IL-10, while enhancing Treg activity and suppressing Teffs. The figure was created with BioRender.

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