PD-1 and its ligands in T-cell immunity
Introduction
Pathways in the B7–CD28 family critically regulate the balance between the stimulatory and inhibitory signals needed for defense against microbes and for self-tolerance [1, 2, 3]. These pathways provide second signals that can regulate the activation, inhibition and fine-tuning of T-cell responses. One of the surprises of the past few years has been the abundance of inhibitory pathways within the B7–CD28 family that can attenuate T-cell responses and promote T-cell tolerance.
This review focuses on recent advances in our understanding of one of the newer pathways in the B7–CD28 family, the PD-1–PD-L pathway. This pathway consists of the programmed death (PD)-1 receptor and its two ligands: PD-L1 (also known as B7-H1 or CD274) and PD-L2 (also called B7-DC and CD273). PD-1 is inducibly expressed on CD4+ T cells, CD8+ T cells, NKT cells, B cells and monocytes upon activation. The wide expression of PD-1 contrasts with specific expression of other CD28 family members on T cells. PD-Ls differ in their expression, with PD-L1 being expressed much more broadly than PD-L2. PD-L1 is expressed on B cells, dendritic cells (DCs), macrophages, cultured bone marrow derived mast cells and T cells, and is further upregulated upon activation. PD-L1 and PD-1 are both expressed on CD4+CD25+ T cells, but whether they influence function of these regulatory T cells (T-regs) is not yet clear. PD-L1 is also expressed on a wide variety of non-hematopoietic cell types, including vascular endothelial cells, pancreatic islet cells, astrocytes and keratinocytes, and at sites of immune privilege including the placenta and the eye. Interferons α, β and γ are potent upregulators of PD-L1 expression on antigen-presenting cells (APCs), endothelial cells and epithelial cells. By contrast, PD-L2 is inducibly expressed only on DCs, macrophages and bone marrow derived cultured mast cells. The finding that both PD-L1 and PD-L2 can be expressed on mast cells [4], together with recent work showing that mast cells are required for CD4+CD25+FoxP3+ T-reg-dependent peripheral tolerance [5•], raises the issue of whether the PD-1–PD-L pathway regulates interaction between T-regs and mast cells that mediate immune suppression.
Section snippets
PD-1–PD-L pathway and regulation of T-cell responses
The important inhibitory function of PD-1 was first appreciated by the autoimmune-like phenotype of PD-1−/− mice [3]. PD-1 has been linked to several autoimmune disorders through genetic analyses of human patients. One of the first studies to link a single nucleotide polymorphism (SNP) in the pdcd1 gene that encodes PD-1 with autoimmunity showed that a polymorphism in an intronic regulatory region that functions as a binding site for Runt-related transcription factor 1 (Runx1, also called
The PD-1–PD-L pathway and DC–T cell interactions
Recent reports have evaluated the role of the PD-1–PD-L pathway in regulating the decision to induce protective immunity or to maintain immune tolerance at the level of DC–T cell interactions. In transgenic mice that express immunodominant peptide epitopes from lymphocytic choriomeningitis virus (LCMV) on resting DCs, CD8+ T cells are unresponsive following interaction with resting antigen-bearing DCs, demonstrating the induction of tolerance. By contrast, the in vivo expression of LCMV
DC intrinsic effects and reverse-signaling through PD-L
Although the PD-1–PD-L pathway can negatively regulate T cells, emerging evidence points to an intrinsic role for PD-Ls on DCs [17, 18, 19, 20]. Ligation of PD-L1 or PD-L2 can lead to reverse signaling into the DC that ultimately results in the inhibition of the ensuing immune response. Engaging DCs with soluble PD-1 decreased the expression of DC maturation markers (CD40, B7-1 and B7-2) and increased IL-10 production, suggesting that a suppressive phenotype is attained by DCs through PD-L
PD-L1 expression and tolerance to self-antigen in tissues
PD-L1 expression on tissues appears to be crucial to shield peripheral tissues from autoimmune attack. The expression of PD-L1 on parenchymal cells has raised the interesting possibility that T cells that express PD-1 might productively interact with non-classical APCs. Recent evidence indicates that interactions between parenchymal cells and lymphocytes utilize PD-1–PD-L1 signaling to maintain tolerance. In the nonobese diabetic (NOD) mouse model of spontaneous autoimmune diabetes, both PD-1−/−
Roles of the PD-1–PD-L pathway in regulating immune responses to infection
Recent studies indicate that the PD-1–PD-L pathway not only has important roles in regulating self-tolerance but also has key roles in regulating anti-microbial immune defense. This pathway controls immune responses to microorganisms that cause acute or chronic infection.
Several studies suggest that this pathway may control immune-mediated tissue damage during viral infection. For example, PD-1−/− mice infected with adenovirus developed more severe liver damage but cleared the virus more
Chronic infections and the PD-1–PD-L pathway
A variety of microorganisms that cause chronic infections appear to have exploited the PD-1–PD-L pathway to attenuate anti-microbial immunity and to facilitate persistent infection. During chronic viral infection, the functions of virus-specific CD8+ T cells are often impaired in contrast to the highly functional effector and memory CD8+ T cells generated after acute infection or vaccination [29]. The persistence of non-functional virus-specific CD8+ T cells, termed ‘exhaustion’, has been
PD-L and immune evasion by tumors
Tumors also appear to exploit PD-L1 to evade detection by the immune system. PD-L1 expression on carcinomas is correlated with poor clinical prognosis of renal [37•] and gastric [38] carcinomas, breast cancer carcinomas [39] and esophageal cancers [40]. In vitro blockade of PD-L1 enhances tumor-specific T-cell responses [41]. In a gene expression profiling analysis, PD-L2 was found to be associated with diffuse large B cell lymphoma and Hodgkin's lymphoma [42]. PD-1−/− mice have an increased
Conclusions
The PD-1–PD-L pathway is a key regulator of the crucial balance between stimulatory and inhibitory signals needed for effective immune responses to microbes and for self-tolerance. Studies in the past year demonstrate that the PD-1–PD-L pathway can control self-tolerance in numerous ways. PD-L1 and PD-L2 might bidirectionally regulate DC–T cell interactions. It is possible that PD-Ls on the DC not only regulate whether a T cell is activated or functionally silenced but also influence APC
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
This work was supported by grants from the National Institutes of Health (NIH) to AHS, the National Multiple Sclerosis Society (to AHS and LMF) and the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative. Because of space restrictions, we were able to cite only a fraction of the relevant literature and apologize to colleagues whose contributions may not be appropriately acknowledged.
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