Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells

Abstract

IntroductionAmong the numerous molecules that regulate T-cell function, the inhibitory receptor PD-1 and its 2 B7 family ligands, B7-H1(PD-L1) and B7-DC (PD-L2), seem to play important roles in microbial immunity, tumor immunity, and autoimmunity. 1-6 PD-1 contains a classic immunoreceptor tyrosine-based inhibitory motif (ITIM) and binds the phosphatase SHP-2. 7 PD-1 engagement has been shown to induce T cell apoptosis and to inhibit proliferative responses and cytokine release in vitro in response to TCR engagement. 8,9 Definitive evidence that PD-1 represents an inhibitory receptor comes from analysis of PD-1 knockout mice, which develop strain-specific autoimmune syndromes later in life. 10,11 The more delayed and tissue-specific autoimmune phenotypes of PD-1 knockout mice contrast markedly with the multiorgan autoimmunity observed within the first few weeks of birth for CTLA-4 knockout mice. [12][13][14] These findings support the notion that PD-1 is part of a system that fine-tunes immune responses, in contrast to the "on-off switch" mediated by the B7-1/B7-2-CD28/CTLA-4 system. Most of the inhibitory roles of PD-1 on T-cell responses have been attributed to its interaction with B7-H1. In vivo, B7-H1:PD-1 interactions have been documented to inhibit T-cell-effector responses to both tumors as well as to normal peripheral tissues. It is highly likely that the up-regulation of B7-H1 by tumors that serves to protect them from immune attack is a reflection of the normal expression of B7-H1 within peripheral tissues that represents a natural mechanism for regulating tissue injury by effector T cells. B7-H1 is expressed constitutively on subsets of macrophages, B cells, and thymocytes as well as certain nonhematopoietic cells within many organs. 1,15 This PD1 ligand is inducible on dendritic cells and all lymphocytes, as well as endothelial cells, epithelial cells, myocytes, and mesenchymal cells. 1,15 B7-H1 plays a well-documented role in down-modulating T-cell responsesparticularly CD8 responses-within the liver, where it is expressed on cells lining the sinusoids. 16 B7-H1 knockout mice display decreased apoptosis of intrahepatic CD8 cells as well as enhanced CD8 responses within the liver after infections with microbes such as adenovirus and Listeria monocytogenes. 16,17 The role of B7-H1: PD-1 interactions extends beyond the liver. For example, autoimmune diabetes is exacerbated in diabetes-prone mouse strains crossed onto a B7-H1-null background. 18 Further evidence for the role of the B7-H1:PD-1 interaction in effector T-cell responses has come from recent studies demonstrating that "exhausted" CD8 cells from mice chronically infected with the clone 13 strain of LCMV express high levels of PD-1. 6 This inactivated functional phenotype can be reversed in mice treated with blocking antibodies to B7-H1, emphasizing the important role of the B7-H1:PD-1 interaction in down-modulating effector immune responses. To date, however, the earliest point at which a role for B7-H1/PD-1 in the CD8 T cell response has b...

Premature Terminal Exhaustion of Friend Virus-Specific Effector CD8+ T Cells by Rapid Induction of Multiple Inhibitory Receptors

“…These observations strikingly resemble the early events in FV infection, which is represented by the rapid expansion of virus-infected, PD-L1 Hi erythroblasts and rapid exhaustion of CD8 + T cells, although the severity of virus infection and CD8 + T cell exhaustion between these models differs in degree. Considering that CD8 + T cells upregulate inhibitory molecules at very early stages under the tolerogenic environment and that the negative signals provided at this stage have a profound impact on the early fate-decision of CD8 + T cells (44,58), prevention of the potential negative signals during the priming/differentiation phase is rational for rescuing virus-specific CD8 + T cells from terminal exhaustion and for the effective elimination of virus-infected cells, as we successfully demonstrated in the current study.…”

“…Because high-level expression of PD-1 can be observed by the time of first cell division under the tolerogenic environment (44), and the massive expansion of FV-infected erythroid cells begins as early as 1 wk postinfection (45), it is possible that Ag-specific CD8 + T cells rapidly enter the state of full functional exhaustion during the priming/ differentiation phase in FV-infected animals. To examine this, we next treated FV-infected mice with Abs to PD-1 and Tim-3 between days 2-14 postinfection, thereby attempting to ensure that virus-specific CD8 + T cells were primed and differentiated in the absence of negative signals from these inhibitory receptors (Fig.…”

Activator protein 1 suppresses antitumor T-cell function via the induction of programmed death 1

“…As a common target for both TCR and cytokine signaling, c-Fos (AP-1) could be a primary factor that is responsible for the activation of PD-1 transcription during tumor progression, which was indeed confirmed by analysis of the AP-1-binding site mutant mouse. c-Fos (AP-1)-mediated PD-1 expression suppresses antitumor T-cell function; however, this transcriptional regulation may be an important factor in the avoidance of autoimmune diseases given that the rapid upregulation of PD-1 is essential for T-cell tolerance (33).…”

PD-1-Mediated Suppression of IL-2 Production Induces CD8+ T Cell Anergy In Vivo

“…PD-1 is reported to be induced on T cells before their first division following Ag encounter in vivo, and the administration of blocking Abs for PD-1 or PD-L1 at the time of Ag encounter markedly enhances the production of effector cytokines from the T cells 4 days later (19). Together with our observations, this finding suggests that the rapid induction of PD-1 and constitutive expression of its ligand PD-L1, observed in Ag-injected 2C rag2…”