Figure 2

Inhibitory signaling events at the DC-T cell interjunction leading to T-cell inhibition in HIV infection. The inhibitory molecules expressed on APCs and T cells regulate the TCR-mediated signals. CTLA-4 and PD-1 recruit the key protein tyrosine kinases SHP-1 and SHP-2 leading to decreased IL-2 production and T-cell inhibition. CTLA-4 and PD-1 block CD28-mediated increase of glucose metabolism by interfering with Akt phosphorylation. PD-1 blocks the activation of phosphatidylinositol-3-kinase and CTLA-4 acting further downstream. LAG-3 induces high level of T-cell inhibition independent of other inhibitory molecules. LAG-3 functions by binding to the CD3/TCR complex where it inhibits CD3/TCR signaling and TCR-induced Ca²⁺-fluxes. 2B4-mediated CD8⁺ T-cell inhibition occurs via 2B4 binding to CD48 leading to recruitment of EAT2 adaptor molecule. TRAIL can interact with DR receptors to induce T-cell suppression without initiating apoptosis. Engagement of BTLA on T cells with HVEM inhibits TCR-mediated signaling via ITIM motifs and recruitment of SHP. Likewise CD160 also engages with the HVEM inhibiting the cell cycle functions of T-cell proliferation. Similarly, TIM-3-galectin9/phosphatidylserine and soluble E-cadherin-KLRG engagements could also lead to T-cell inhibition.