The Role of PD-1 in Acute and Chronic Infection

Abstract

PD-1 as an immune checkpoint molecule down-regulates T cell activity during immune responses in order to prevent autoimmune tissue damage. In chronic infections or tumors, lasting antigen-exposure leads to permanent PD-1 expression that can limit immune-mediated clearance of pathogens or degenerated cells. Blocking PD-1 can enhance T cell function; in cancer treatment PD-1 blockade is already used as a successful therapy. However, the role of PD-1 expression and blocking in the context of acute and chronic infections is less defined. Building on its success in cancer therapy leads to the hypothesis that blocking PD-1 in infectious diseases is also beneficial in acute or chronic infections. This review will focus on the role of PD-1 expression in acute and chronic infections with virus, bacteria, and parasites, with a particular focus on recent studies regarding PD-1 blockade in infectious diseases.

Keywords: PD-1; PD-L1; PD-L2; T cell exhaustion; acute infection; checkpoint inhibitor; chronic infection; infectious disease.

Figure 1

T cell differentiation during acute vs. chronic infections. When pathogenic peptides are presented by major histocompatibility complex (MHC) to naive T cells during infection, corresponding T cells are activated and differentiate into effector T cells specific for the pathogen. During acute infection, the immune system is able to specifically target the pathogen and eradicate it. During this process, memory T cells develop and confer immunological memory against recurrent infection. In contrast, during chronic infection the persistent load of pathogenic peptides leads to permanent stimulation of T cells, which promotes T cell exhaustion. T cell exhaustion is in part defined by the upregulation of coinhibitory receptors such as PD-1, LAG-3, and Tim-3. These receptors inhibit T cells by decreasing IL-2 production, proliferation, and the threshold for apoptosis.

Figure 2

(A) PD-1 signaling pathway. The binding of PD-L1 or PD-L2 to its receptor PD-1 results in the phosphorylation of PD-1's ITSM and ITIM tyrosine motifs, which are located on its cytoplasmic domain. Phosphorylation leads to the recruitment of protein tyrosine phosphatases, such as SHP2. SHP2 subsequently inhibits two important pathways: One, it competes with kinases to prevent the activation of PI3K by phosphorylation. This inhibits phosphorylation of PIP2 to PIP3, thereby inhibiting Akt activation. Deactivation of serine-threonine kinase Akt reduces T cell proliferation, increases apoptosis, and promotes T cell exhaustion. Effector functions such as cytokine production and cytolytic function are also reduced. Two, SHP2 inhibits the Ras-MEK-ERK pathway. Dephosphorylation of ZAP-70 and LCK antagonize the positive downstream effects of the MHC-TCR pathway, leading to deactivation of PLC-γ, Ras-GRP1 and MEK/ERK1. ERK1 normally activates transcription factors that induce T cell proliferation and differentiation. Thus, decreased ERK1 activation reduces proliferation and differentiation potential. (B) Blockade of PD-1. In the presence of a PD-1 blocking antibody, the engagement of PD-1 and its ligands is inhibited. Consequently, SHP2 is not activated and neither PI3K/Akt pathway nor Ras-MEK-ERK pathway are repressed. Activated AKT and ERK support T cell cytokine production, proliferation, and differentiation. Furthermore, PD-1 blockade reduces T cell exhaustion and the rate of apoptosis. ITSM, immunoreceptor tyrosine-based switch motif; ITIM: immunoreceptor tyrosine-based inhibition motif; SHP2, Src homology region 2 domain-containing phosphatase 2; PI3K, phosphoinositide 3-kinase; PIP2, phosphoinositide-3,4-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; Ras, rat sarcoma; MEK, MAK-/ERK-kinase; ERK1, extracellular-signal regulated kinases 1; Zap-70, zeta-chain-associated protein kinase 70; LCK, lymphocyte-specific protein tyrosine kinase; PLC-γ, Phosphoinositide phospholipase C-γ.