PD-1and its ligands in T-cell immunity
Mary E Keir,Loise M Francisco and Arlene H Sharpe
The past year has seen significant advances in our understanding of the critical roles of negative immunoregulatory signals delivered by the programmed death 1(PD-1)–PD-1ligand(PD-L)pathway in regulating T-cell activation and tolerance.Emerging evidence indicates that PD-Ls play an essential role on dendritic cells(DCs),both directly during DC–T cell interactions and indirectly through signaling into the DC.Recent studies point to a novel role for PD-L1in maintaining tissue tolerance.Finally,PD-1has recently been shown to be highly expressed on exhausted T cells during chronic viral infection,and blockade of PD-1or PD-L1can revive exhausted T cells,enabling them to proliferate and produce effector cytokines.
Addresses
Department of Pathology,Harvard Medical School and Brigham and Women’s Hospital,NRB77Avenue Louis Pasteur,Boston,
MA02115,USA
Corresponding author:Sharpe,Arlene H
(arlene_sharpe@hms.harvard.edu)
Current Opinion in Immunology2007,19:309–314
This review comes from a themed issue on
Lymphocyte activation
Edited by Ulrich von Andrian and Federica Sallusto
Available online12th April2007
0952-7915/$–see front matter
#2006Elsevier Ltd.All rights reserved.
DOI10.i.2007.04.012
Introduction
Pathways in the B7–CD28family critically regulate the balance between the stimulatory and inhibitory signals needed for defense against microbes and for self-tolerance[1–3].These pathways provide second signals that can regulate the activation,inhibition andfine-tuning of T-cell responses.One of the surprises of the past few years has been the abundance of inhibitory pathways within the B7–CD28family that can attenuate T-cell responses and promote T-cell tolerance.
This review focuses on recent advances in our under-standing 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)-1receptor and its two ligands: PD-L1(also known as B7-H1or CD274)and PD-L2(also called B7-DC and CD273).PD-1is inducibly expressed on CD4+T cells,CD8+T cells,NKT cells,B cells and monocytes upon activation.The wide expression of PD-1contrasts with specific expression of other CD28 family members on T cells.PD-Ls differ in their expres-sion,with PD-L1being expressed much more broadly than PD-L2.PD-L1is expressed on B cells,dendritic cells (DCs),macrophages,cultured bone marrow derived mast cells and T cells,and is further upregulated
upon acti-vation.PD-L1and PD-1are 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 a,b and g are potent upregulators of PD-L1 expression on antigen-presenting cells(APCs),endo-thelial cells and epithelial cells.By contrast,PD-L2is inducibly expressed only on DCs,macrophages and bone marrow derived cultured mast cells.Thefinding that both PD-L1and PD-L2can be expressed on mast cells[4], together with recent work showing that mast cells are required for CD4+CD25+FoxP3+T-reg-dependent per-ipheral 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.
PD-1–PD-L pathway and regulation of
T-cell responses
The important inhibitory function of PD-1wasfirst appreciated by the autoimmune-like phenotype of PD-1À/Àmice[3].PD-1has been linked to several auto-immune disorders through genetic analyses of
human patients.One of thefirst studies to link a single nucleotide polymorphism(SNP)in the pdcd1gene that encodes PD-1with autoimmunity showed that a polymorphism in an intronic regulatory region that functions as a binding site for Runt-related transcription factor1(Runx1,also called AML-1),which is thought to play a regulatory role in hematopoiesis and may affect PD-1expression,is associ-ated with susceptibility to systemic lupus erythematosus (SLE)[6].The same SNP was subsequently linked to rheumatoid arthritis(RA)[7]and to type1diabetes mellitus[8].Further work has shown that other SNPs in the pdcd1gene are associated with RA[9],SLE[10] and ankylosing spondylitis[11].Most of these mutations are found in conserved regions in intronic sequences, which might affect transcription factor binding and thereby modulate expression of the PD-1protein[12]. Although PD-1has been well characterized as a negative regulator of T cells,the roles that PD-Ls play in T-cell activation are only beginning to be understood.Whereas many studies have demonstrated that PD-Ls can inhibit
T-cell proliferation and cytokine production,others have found that PD-Ls enhance T-cell activation.The reasons for these contradictory results are not yet clear.Recent work shows that PD-L1can increase T-cell proliferation by inhibiting interferon-g(IFN-g)-induced nitric oxide production.When macrophages are used as APCs,anti-PD-L1and anti-PD-1monoclonal antibodies(mAbs) increase IFN-g and interleukin2(IL-2)production by T cells,but paradoxically inhibit their proliferation.This effect was found to be caused by IFN-g-dependent induction of nitric oxide by macrophages[13],which leads to inhibition of T-cell proliferation.Thesefindings suggest that the positive effects of PD-Ls can be explained,at least in part,by the inhibition of negative signaling.Although a second stimulatory receptor for PD-Ls has been postulated,it has yet to be identified.Some data suggest that PD-L1and/or PD-L2might signal bidirectionally,as will be discussed below.
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 rest-ing antigen-
bearing DCs,demonstrating the induction of tolerance.By contrast,the in vivo expression of LCMV epitopes on the same resting DCs induces priming rather than tolerance in PD-1À/ÀCD8+T cells[14 ].Interest-ingly,the loss of PD-1on CD8+T cells had a much greater effect on abrogating CD8+tolerance than CTLA-4blockade alone.However,the combination of anti-CTLA-4mAb and PD-1À/ÀCD8+T cells further enhanced priming,suggesting an additive effect of PD-1and CTLA-4.
PD-L expression on DCs can also attenuate the effects of pathogenic CD4+T cells and macrophages.DCs geneti-cally modified to overexpress PD-L1and myelin oligo-dendrocyte glycoprotein peptide(MOG)in the context of MHC class II could ameliorate experimental auto-immune encephalitis(EAE)and diminish macrophage, CD4+and CD8+T-cell infiltration of the spinal cord[15 ]. The relative role of PD-L1versus PD-L2on the DC is of interest,with other work showing overlapping function in the ability of PD-L to inhibit production of IL-2and effector cytokines by T cells[16 ].These data suggest an integral role for PD-1in receiving signals from DCs that control T-cell tolerance versus activation.
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 intr
insic role for PD-Ls on DCs[17–20].Ligation of PD-L1or PD-L2can lead to reverse signaling into the DC that ulti-mately results in the inhibition of the ensuing immune response.Engaging DCs with soluble PD-1decreased the expression of DC maturation markers(CD40,B7-1and B7-2)and increased IL-10production,suggesting that a suppressive phenotype is attained by DCs through PD-L back-signaling[20].Interestingly,direct ligation of PD-L2on murine DCs with a pentameric anti-PD-L2anti-body isolated from patients with Waldenstrom’s macro-globulinemia enhances antigen uptake and presentation by immature DCs[18].Although DCs treated with anti-PD-L2mAb do not upregulate the expression of MHC class II or B7costimulatory molecules,they produce the proinflammatory cytokines tumor necrosis factor a(TNF-a)and IL-6and stimulate naı¨ve T-cell proliferation. Further analysis of the genetic program induced by PD-L2cross-linking reveals an increased expression of gene products capable of enhancing DC migration to lymph nodes,activation of naı¨ve T cells and survival [19].Thesefindings suggest an intrinsic function for PD-L1and/or PD-L2on the DC itself.Earlier studies by Grohmann et al.[21,22]have shown that B7family members not only function as ligands,but that they are functional receptors that have profound inhibitory and stimulatory effects on the DC.Further studies are needed to determine how PD-Ls signal into the DC,and what downstream effects this DC has in influencing whether immunity or tolerance ensues.
PD-L1expression and tolerance to
self-antigen in tissues
PD-L1expression on tissues appears to be crucial to shield peripheral tissues from autoimmune attack.The expression of PD-L1on 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 par-enchymal cells and lymphocytes utilize PD-1–PD-L1 signaling to maintain tolerance.In the nonobese diabetic (NOD)mouse model of spontaneous autoimmune dia-betes,both PD-1À/À[23]and PD-L1À/À[16 ]NOD mice share a phenotype of rapid-onset diabetes.PD-L1 expression in the pancreas,either on b cells or on vascular endothelium,is protective against autoimmune diabetes in the NOD mouse,as demonstrated by bone marrow chimera experiments[16 ].Whether expression of PD-L1in these locations is protective because of direct interactions with T cells or through another cell type, such as DCs or T-regs,is unclear.Tolerance induction by adoptive transfer of antigen-bearing splenocytes in the NOD model is mediated via PD-1–PD-L1interactions, but requires PD-L1expression on host tissues rather than on the transferred cells[24].Data in the EAE model showed that strain-specific differences in disease induc-tion do not correlate with altered levels of PD-L1or PD-L2on traditional APCs,indicating that tissue expression
310Lymphocyte activation
of the PD-L might be important in this autoimmune model as well[25].Interestingly,PD-L1also functions in the placenta to promote fetal–maternal tolerance[26 ]. Together,these data indicate that expression of PD-L1 on parenchymal cells might protect these tissues from self-reactive lymphocytes.B7-H3and B7-H4,newly characterized members of the B7superfamily,also are expressed on non-hematopoietic cells and can inhibit T-cell responses[1].It is possible that they function similarly to control peripheral tolerance.
How T cells receive PD-1signals along with an antigen-specific signal remains to be determined.Because most parenchymal cells express MHC class I,PD-L1expres-sion might be most effective against self-reactive CD8+T cells.However,protection from CD4+effectors by par-enchymal PD-L1expression has been described[16], suggesting that indirect interactions with other cell types (e.g.T-regs)might be required.Alternatively,vascular endothelium has been shown to express both MHC class I and II as well as PD-L1[27],suggesting that PD-L1 might attenuate CD4+effectors and/or regulate transmi-gration of lymphocytes into tissues.Other microenviron-ments might utilize PD-L to generate and maintain tolerance.It was recently demonstrated that PD-L2is important in oral tolerance,with both CD4+and CD8+T cells failing to induce tolerance in ovalbumin-fed PD-L2À/Àmice[17].
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-1À/Àmice infected with adenovirus developed more severe liver damage but cleared the virus more rapidly than wild-type mice[28].Thisfinding suggests that PD-1might limit potentially detrimental consequences of anti-microbial effector responses. 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 per-sistent infection.During chronic viral infection,the func-tions 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 vaccina-tion[29].The persistence of non-functional virus-specific CD8+T cells,termed‘exhaustion’,has been observed during experimental chronic infections,such as chronic LCMV infection in mice and simian immunodeficiency virus infection of primates,as well in human infections with human immunodeficien
cy virus,hepatitis
B virus, hepatitis
C virus(HCV)and human T lymphotropic virus [29].T-cell exhaustion represents a spectrum of defects. As the magnitude of the viral load increases,virus-specific T cells become more functionally impaired.Proliferative potential and IL-2production are lost early,whereas effector cytokine production and cytolytic functions are lost later.Recent studies have shown that PD-1is highly expressed by CD8+T cells during chronic LCMV infec-tion,HIV infection and HCV infection[30 –34 ]. Studies in the chronic LCMV model demonstrate that the PD-1upregulation is functionally significant and that the PD-1–PDL-1pathway plays a crucial role in regulating T-cell exhaustion during this infection[30 ].When anti-PD-1or anti-PD-L1blocking antibodies were adminis-tered during chronic LCMV infection,virus-specific CD8+T-cell responses were strikingly enhanced. LCMV-specific CD8+T cells greatly increased in number and produced more IFN-g and TNF-a per cell.Signifi-cantly,these reinvigorated virus-specific CD8+T cells markedly reduced the viral load.
Recent work has extended these observations to HIV and HCV infection[31 –33 ].Several groups have demon-strated that blockade of the PD-1–PD-L pathway leads to increased T-cell proliferation
and TNF-a,IFN-g and granzyme B production,indicating improved T effector cell function of HIV-specific CD8+T cells.Remarkably, anti-PD-L1blockade also restored CD4+T-cell prolif-erative responses to HIV antigen.Similarly,anti-PD-L1 enhanced proliferation of HCV-specific CD8+T cells,but CD8+effector functions were not examined.Taken together,thesefindings suggest that the PD-1–PD-L pathway might be operating to deter anti-viral T-cell responses during chronic HIV and HCV infection,and suggest that blockade of this pathway might provide a new therapeutic approach to revive dysfunctional T cells. It appears that PD-1also might serve as a useful marker on virus-specific CD8+T cells to indicate the degree of T-cell exhaustion and disease severity[31 –33 ].The level and percentage of PD-1expression on HIV-specific CD8+T cells correlates with viral load,declining CD4 counts,and decreased capacity of CD8+T cells to pro-liferate to HIV antigen in vitro.PD-1expression on HIV-specific CD8+T cells decreased upon effective highly active anti-retroviral therapy therapy,suggesting that high viral load stimulates PD-1expression and functional exhaustion.Similarly,PD-1might be a marker for disease progression in HCV infection.During acute HCV infec-tion,PD-1is upregulated on HCV-specific CD8+T cells,declines in patients with resolving infection,but remains high in patients who develop chronic infection [34 ].
PD-1and its ligands in T-cell immunity Keir,Francisco and Sharpe311
The PD-1–PD-L pathway also has been exploited by worms to evade immune defenses.PD-L1and PD-L2 expression are upregulated on activated macrophages induced during Taenia crassiceps infection[35].Blockade of PD-L1,PD-L2or PD-1significantly reduced suppres-sion of in vitro T-cell proliferation by macrophages from Taenia-infected mice.During Schistosoma mansonii infec-tion of mice,macrophages express high levels of PD-L1 and modest levels of PD-L2[36].Anti-PD-L1completely ablated the ability of these macrophages to suppress anti-CD3activation of CD4+or CD8+T-cell proliferation in vitro,whereas anti-PD-L2had no effect.PD-L1expres-sion on macrophages from infected mice declines after 12weeks of infection,concomitant with the break in T-cell anergy.Thus,a variety of pathogens have utilized the PD-1–PD-L pathway to manipulate host immune defenses to enable pathogen persistence.
机器人定位
技术PD-L and immune evasion by tumors Tumors also appear to exploit PD-L1to evade detection by the immune system.PD-L1expression 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-L2was found to be associated with diffuse large B cell lymphoma and Hodg-kin’s lymphoma[42].PD-1À/Àmice have an i
虚拟演播室
ncreased resistance to tumor engraftment and growth that corre-lates with increased effector cytokine production and the preservation of tumor-specific T-cell responses in tumor-bearing mice[43 ].The shared expression of PD-L on tumors and on tissues that are the target of autoimmune attack(such as the pancreas)might complicate thera-peutic blockade strategies for tumor immunotherapy.Lo-ng-term treatment of patients with PD-1or PD-L1 neutralizing antibodies might induce autoimmune responses as an unintended consequence of therapy—a possibility that will require further study. 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 demon-strate that the PD-1–PD-L pathway can control self-tolerance in numerous ways.PD-L1and PD-L2might 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 function.PD-L1on non-hematopoietic cells could be key for mediating tissue tolerance as well as controlling the intensity of T-cell effector responses. Microbes and tumors have exploited this pathway to attenuate anti-microbial and anti-tumor immunity,and dysfunctional T cells that express PD-1in chronic infec-tion or tumors provide a novel therapeutic target.The recent appreciation of the 教学
植物园 inhibitory functions of the PD-1–PD-L pathway raises many questions.We do not yet know the functional significance of PD-1on B cells and macrophages;PD-1might not only regulate T-cell tolerance but might also regulate B-cell tolerance and the function of inhibitory macrophages.Little is known about the stimuli for expression of PD-1or its ligands.One major difference between PD-L1and PD-L2is that PD-L1is constitutively expressed and moderately upre-gulated upon inflammation whereas PD-L2is exclusively found on activated DCs,macrophages and mast cells. The spatial and temporal differences in PD-L1and PD-L2expression could explain how PD-L1and PD-L2have synergistic as well as unique functions. The many potential bidirectional interactions between PD-1and PD-L1on B cells,T cells and macrophages might function as a communication conduit that links the adaptive and innate immune system.An important and relatively unexplored area is the molecular mechanisms of signaling through PD-1and its ligands.It is crucial to understand how this pathway mediates its inhibitory effects.Such studies will not only provide insights into the fundamental functions of the PD-1–PD-L pathway in regulating T-cell activation and tolerance but will also facilitate manipulation of this pathway therapeutically. 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 t
hrough 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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PD-1and its ligands in T-cell immunity Keir,Francisco and Sharpe313
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