CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms

Abstract

CTLA-4 and PD-1 are receptors that negatively regulate T-cell activation. Ligation of both CTLA-4 and PD-1 blocked CD3/CD28-mediated upregulation of glucose metabolism and Akt activity, but each accomplished this regulation using separate mechanisms. CTLA-4-mediated inhibition of Akt phosphorylation is sensitive to okadaic acid, providing direct evidence that PP2A plays a prominent role in mediating CTLA-4 suppression of T-cell activation. In contrast, PD-1 signaling inhibits Akt phosphorylation by preventing CD28-mediated activation of phosphatidylinositol 3-kinase (PI3K). The ability of PD-1 to suppress PI3K/AKT activation was dependent upon the immunoreceptor tyrosine-based switch motif located in its cytoplasmic tail, adding further importance to this domain in mediating PD-1 signal transduction. Lastly, PD-1 ligation is more effective in suppressing CD3/CD28-induced changes in the T-cell transcriptional profile, suggesting that differential regulation of PI3K activation by PD-1 and CTLA-4 ligation results in distinct cellular phenotypes. Together, these data suggest that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.

TGF-β in intestinal lymphoid organs contributes to the death of armed effector CD8 T cells and is associated with the absence of virus containment in rhesus macaques infected with the simian immunodeficiency virus

“…Thus, TGF-b could be the arming signal 1 and the death molecules (signal 2), the executioners of the effector/memory CD8 þ T cells in Mes LNs. Moreover, given that IDO is responsible for downmodulating T-cell proliferation, 11 while PD-1 limits glucose metabolism, 37 their concerted expression may be a multi-pronged strategy to enforce T lymphocyte inhibition by disrupting cellular metabolism which is required for cell survival. Thus, triggering multiple negative regulators of T-cell activation will likely be far more effective at dysregulating T-cell activation during SIV infection than the actions of any single inhibitor.…”

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

“…PD-1 has two ligands, PD-L1 (also known as B7-H1 or CD274), constitutively expressed by many tissues and upregulated on activation [3], and PD-L2 (also known as B7-DC or CD273), expressed primarily by activated DC and macrophages [4]. Upon ligation by either molecule, PD-1 recruits the SHP-1 and SHP-2 phosphatases to its ITSM, leading to dephosphorylation of effector molecules downstream of the TCR and the BCR, such as Syk and phosphoinositide 3-kinase (PI3K), as well as decreasing CD28-mediated activation of PI3K [5]. Without PD-1, C57BL/6 mice develop a lupus-like glomerulonephritis and arthritis [6], BALB/c mice develop a fatal cardiomyopathy due to autoantibody to troponin 1 [7], and NOD mice show an earlier onset and more severe diabetes than wild-type (WT) NOD mice [8].…”

BRAF mutations in non-small cell lung cancer: has finally Janus opened the door?

“…Therapies that target immune system check-points, such as CTLA-4 and PD-1, were designed to enhance hostís immune system, oppose tumor immune evasion and generate an effective immune response against tumor cells. CTLA-4 is a transmembrane receptor expressed on T-cells that exerts an inhibitory effect over T-cell stimulation and activation (Parry et al, 2005). Ipilimumab is an anti CTLA-4 fully human monoclonal antibody.…”

“…(NCT01285609) PD-1 is a membrane receptor present on T lymphocytes. When activated by its ligands, PDL-1 and PDL-2, PD-1 exerts an inhibitory effect over T-cells (Parry et al, 2005). PD-1/PDL-1 pathway is also involved in tumor evasion and immune tolerance.…”