PD-1 coinhibitory signals: The link between pathogenesis and protection

Abstract

In the majority of HIV-1 infected individuals, the adaptive immune response drives virus escape resulting in persistent viremia and a lack of immune-mediated control. The expression of negative regulatory molecules such as PD-1 during chronic HIV infection provides a useful marker to differentiate functional memory T cell subsets and the frequency of T cells with an exhausted phenotype. In addition, cell-based measurements of virus persistence equate with activation markers and the frequency of CD4 T cells expressing PD-1. High-level expression of PD-1 and its ligands PD-L1 and - L2 are found on hematopoietic and non-hematopoietic cells, which are regulated by chronic antigen stimulation, Type 1 and Type II interferons (IFNs), and homeostatic cytokines. In HIV infected subjects, PD-1 levels on CD4 and CD8 T cells continue to remain high following combination anti-retroviral therapy (cART). System biology approaches have begun to elucidate signal transduction pathways regulated by PD-1 expression in CD4 and CD8 T cell subsets that become dysfunctional through chronic TCR activation and PD-1 signaling. In this review, we summarize our current understanding of transcriptional signatures and signal transduction pathways associated with immune exhaustion with a focus on recent work in our laboratory characterizing the role of PD-1 in T cell dysfunction and HIV pathogenesis. We also highlight the therapeutic potential of blocking PD-1-PD-L1 and other immune checkpoints for activating potent cellular immune responses against chronic viral infections and cancer.

CD8 + T Cell Exhaustion, Suppressed Gamma Interferon Production, and Delayed Memory Response Induced by Chronic Brucella melitensis Infection

“…This suggests that when placed into a fresh environment lacking chronic brucellosisdriven stimulation, these "preexhausted" CD8 ϩ T cells may then have suffered too much antigenic insult upon challenge to transition to effectors and become rapidly exhausted. It is important to note that because PD-1 and LAG-3 are intimately involved in survival, proliferation, and cell cycle progression, the explanation for the loss of exhausted cells in nonchallenged recipients 5 days after transfer remains to be determined (40,41). Having now confirmed the presence of a considerable population of exhausted cells in mice with chronic brucellosis, future experiments will address the specific fate of these exhausted cells by magnetic isolation prior to transfer.…”

Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

“…The PD-1/PD-L1 pathway is a key immune checkpoint that helps regulate normal self-tolerance, but is now known to play a key role in damping immune responses to persistent antigenic stimuli such as chronic viral infections and many malignancies (47,48). As such, mAbs that block PD-1 or PD-L1 enable "exhausted" T cells to regain normal functional capacities, secrete proinflammatory cytokines, and support productive immune responses (49)(50)(51).…”

Human T Cells Engineered To Express a Programmed Death 1/28 Costimulatory Retargeting Molecule Display Enhanced Antitumor Activity

“…PD1 has been shown to reduce the levels of ERK phosphorylation (37). Thus, we wanted to assess how PD1/28 expression would impact on pERK expression.…”