The function of programmed cell death 1 and its ligands in regulating autoimmunity and infectionArlene H Sharpe1, E John Wherry2, Rafi Ahmed3 & Gordon J Freeman4

The programmed cell death 1 (PD-1) surface receptor binds to two ligands, PD-L1 and PD-L2. Studies have shown that PD-1–PD-L interactions control the induction and maintenance of peripheral T cell tolerance and indicate a previously unknown function for PD-L1 on nonhematopoietic cells in protecting tissues from autoimmune attack. PD-1 and its ligands have also been exploited by a variety of microorganisms to attenuate antimicrobial immunity and facilitate chronic infection. Here we examine the functions of PD-1 and its ligands in regulating antimicrobial and self-reactive T cell responses and discuss the therapeutic potential of manipulating this pathway.

The receptor ‘programmed cell death 1’ (PD-1; also called CD279) is inducibly expressed on CD4+ T cells, CD8+ T cells, natural killer T cells, B cells and activated monocytes1–3. PD-1 expression is induced by T cell receptor (TCR) or B cell receptor signaling and is augmented by stimulation with tumor necrosis factor4. The two PD-1 ligands differ in their expression patterns, with expression of PD-L2 being much more restricted than PD-L1 expression1–3,5. PD-L2 (also called B7-DC and CD273) is inducibly expressed on dendritic cells (DCs), macrophages and cultured bone marrow–derived mast cells4. In contrast, PD-L1 (also called B7-H1 and CD274) is expressed constitutively on murine T cells, B cells, DCs, macrophages, mesenchymal stem cells6 and cultured bone marrow–derived mast cells4; PD-L1 expression is further upregulated after activation. Constitutive expression of PD-L1 is lower in humans than in mice7. PD-L1 is also expressed on a wide variety of nonhema-topoietic cell types, including vascular endothelial cells, epithelial cells, muscle cells, hepatocytes, pancreatic islet cells and astrocytes in the brain, as well as at sites of immune privilege, including the placenta and eye. The expression of PD-L1 on nonlymphoid tissues suggests that PD-L1 may regulate self-reactive T cells or B cells and inflammatory responses in these tissues as well as in lymphoid organs. In humans but not in mice, PD-L2 also is expressed on vascular endothelial cells8. Interferon-

α (IFN-α), IFN-β and IFN-γ trigger upregulation of PD-L1 and, to a lesser extent, PD-L2 expression9,10. Interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor strongly stimulate the expres-sion of PD-L2 on DCs in vitro, and IL-10 can induce the expression of PD-L1 on monocytes11. During an active immune response, such as acute infection or graft rejection, PD-L1 is expressed extensively on most cells in the spleen12,13.

The PD-1 receptor is a cell surface monomer consisting of a single immunoglobulin variable-like domain and a cytoplasmic domain containing two tyrosine-based signaling motifs5,14. PD-1 transduces an inhibitory signal when engaged simultaneously with the TCR or B cell receptor but does not transduce a signal when crosslinked alone. Phosphorylation of the second tyrosine residue, located in an immu-noreceptor tyrosine-based switch motif, recruits the phosphatases SHP-2 and, to a lesser extent, SHP-1 to the PD-1 cytoplasmic domain. Recruitment of the phosphatases leads to the dephosphorylation of effector molecules activated by TCR and B cell receptor signaling (such as Syk and phosphatidylinositol-3-OH kinase). In addition, PD-1 signal-ing reduces CD28-mediated activation of phosphatidylinositol-3-OH kinase, thereby suppressing phosphorylation of the kinase Akt, glucose metabolism and expression of the gene encoding the survival protein Bcl-xL. The amount of PD-1 expression and the extent of engagement of PD-1 by its ligands regulate the threshold for T cell activation and quantities of cytokines produced.

The functions of PD-L1 and PD-L2 in T cell activation are only beginning to be understood. Some in vitro studies suggest that PD-L1 and PD-L2 can inhibit T cell proliferation and cytokine production5,15, whereas others indicate that PD-1 ligands enhance T cell activation16,17. The reasons for the contradictory results of those functional stud-ies are not yet clear but may reflect different preparations of PD-L–immunoglobulin fusion protein acting as agonists or antagonists. Although the existence of a second stimulatory receptor capable of binding PD-L proteins has been postulated, it remains to be identified.

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1Department of Pathology, Harvard Medical School and Brigham and Women’s

Hospital, Boston, Massachusetts 02115, USA. 2Immunology Program, The

Wistar Institute, Philadelphia, Pennsylvania 19104, USA. 3Emory Vaccine

Center and Department of Microbiology and Immunology, Emory University

School of Medicine, Atlanta, Georgia 30322, USA. 4Department of Medical

Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard

Medical School, Boston, Massachusetts 02115, USA.

Correspondence should be addressed to A.H.S. (arlene_sharpe@hms.harvard.

edu).

Received 6 December 2006; accepted 17 January 2007; published online 15

February 2007; doi:10.1038/ni1443

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Studies with blocking antibodies and knockout mice indicate important inhibitory functions for the PD-1–PD-L pathway in vivo18–21. Data sug-gest that PD-L1 and/or PD-L2 may signal bidirectionally22–24. Further studies are needed to compare the functions of PD-L1 and PD-L2 on the same cell types and the relative functions of PD-L1 on T cells, antigen-presenting cells (APCs) and nonhematopoietic cells. As both PD-L1 and PD-1 are expressed on T cells, B cells and macrophages, many opportunities exist for bidirectional interactions between PD-L1 and PD-1.

PD-1–PD-L function in tolerance and autoimmunityThe PD-1–PD-L pathway regulates the balance between the stimula-tory and inhibitory signals needed for effective immune responses to microbes and maintenance of self-tolerance, respectively. PD-1 and its ligands influence both central and peripheral tolerance mechanisms. The PD-1–PD-L pathway participates in fate ‘decisions’ at several stages of thymocyte maturation. In the thymus, PD-L1 is expressed broadly in the cortex, whereas PD-L2 expression is restricted to medullary stromal cells7,25. PD-1 is expressed on CD4–CD8– double-negative thymocytes and is required for the normal selection of thymocytes containing pro-ductively rearranged Tcrb genes26. PD-1 expression is upregulated after TCR ligation on CD4+CD8+ double-positive thymocytes, and PD-1 can participate in selection of the αβ TCR repertoire by controlling TCR signaling thresholds. PD-1–PD-L1 interactions modulate positive selection27, and PD-1 also contributes to negative selection28. Such data suggest that the autoimmune phenotype of PD-1-deficient (Pdcd1–/–) mice18,29 may reflect defects in central as well as peripheral tolerance.

Expression of PD-1 ligands in immune-privileged sites such as the placenta and the eye protects such sites from immune responses. In humans, PD-L1 is highly expressed on placental syncytiotrophoblasts and PD-L2 is highly expressed on placental vascular endo-thelial cells7. PD-L1 is also expressed on placental exo-somes that inhibit T cell acti-vation30. Expression of PD-L1 in the placenta increases at the beginning of the second trimester, is upregulated by increased oxygen and is rap-idly lost with low oxygen con-centrations31, and functions in the placenta to promote fetal-maternal tolerance32. Administration of antibody to PD-L1 (anti-PD-L1) but not anti-PD-L2 increases the abortion rate of allogeneic fetuses and is associated with increased T cell infiltration into the placenta. Similarly, PD-L1-deficient female mice have lower allogeneic fetal sur-vival rates than their littermate controls. Studies suggest that PD-1–PD-L1 interactions are key for maintaining immune

privilege in the eye and protecting the eye from activated T cells33–35. In the eye, PD-L1 is expressed constitutively in the cornea, iris–cili-ary body and retina, but neither PD-L2 nor PD-1 is expressed there. Blocking antibodies specific for PD-1 or PD-L1 but not those for PD-L2 accelerate corneal allograft rejection. A PD-L1–immunoglobulin fusion protein that inhibits T cell activation in vitro substantially prolongs cor-neal allograft survival in vivo and almost entirely inhibits inflammatory cell infiltration.

The PD-1–PD-L pathway seems to control peripheral tolerance in sev-eral ways (Fig. 1). PD-L proteins on DCs influence the ‘decision’ between T cell activation and tolerance. An emerging idea is that the presentation of self antigen by unstimulated DCs contributes to peripheral tolerance. Studies indicate that PD-1 is important for the induction of periph-eral CD8+ T cell tolerance by resting DCs in vivo. Wild-type but not Pdcd1–/– CD8+ T cells are made tolerant by resting DCs expressing lym-phocytic choriomeningitis virus (LCMV)–derived cytotoxic T lympho-cyte epitopes under the control of a tamoxifen promoter36. Blockade of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) at the time of tolerance induction triggers a moderate reduction in tolerance and enhances the effects of PD-1 deficiency, suggesting synergistic func-tions for PD-1 and CTLA-4 in peripheral CD8+ T cell tolerance induc-tion by resting DCs. The importance of the PD-1–PD-L pathway in inhibiting self-reactive T cell responses suggests that triggering PD-1 inhibitory signals may be a useful strategy for ameliorating autoimmune diseases. DCs engineered to have high expression of PD-L1 and myelin antigen ameliorate experimental autoimmune encephalitis (EAE) and diminish infiltration of the spinal cord by macrophages and CD4+ and

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Figure 1 The PD-1–PD-L pathway controls autoimmunity. The PD-1–PD-L pathway regulates both the induction and the maintenance of peripheral tolerance. PD-L proteins on tolerogenic DCs can induce T cell tolerance. PD-L1 is constitutively expressed on APCs and T cells and is further upregulated by proinflammatory cytokines; PD-L2 expression is induced by cytokines. PD-1 is upregulated on T cells after they are activated. After initial T cell activation, PD-1–PD-L interactions can limit self-reactive T cell proliferation and cytokine production. Effector functions of self-reactive T cells that migrate to the target tissue (such as the pancreas in type 1 diabetes) may be limited by PD-L1 expressed on nonhematopoietic tissue cells (such as vascular endothelial cells) or islet cells. PD-L1 seems to have a unique function in maintaining tolerance in the target tissue.

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CD8+ T cells37. It is not clear whether the therapeutic effect is due to the induction of anergy in myelin oligodendrocyte glycoprotein (MOG)–specific T cells or the population expansion or differentiation of regula-tory T cells.

PD-L proteins on DCs may also influence APC function. There is some evidence for ‘reverse signaling’ through PD-L proteins into DCs22–24. In in vitro DC cultures, soluble PD-1 decreases the expression of DC maturation markers (CD40, B7-1 and B7-2) and increases IL-10 pro-duction by DCs, resulting in a suppressive DC phenotype. A unique PD-L2-specific immunoglobulin M (IgM) derived from a patient with a human B cell tumor stimulates DC function and the expression of genes capable of enhancing the migration of DCs to lymph nodes, DC survival and T cell activation. Such findings give impetus to further anal-ysis of the involvement of PD-L1 and PD-L2 in the tolerance-inducing functions of DCs.

Much information about the function of PD-1–PD-L pathway in reg-ulating peripheral tolerance and autoimmunity has come from studies of the manipulation of PD-1–PD-L interactions in mouse models of autoimmunity. PD-1–PD-L interactions not only are important in the initial phase of activation and population expansion of self-reactive T cells but also influence subsequent self-reactive T cell effector function and target organ injury. PD-L1 on nonhematopoietic cells seems to be key to mediating tissue tolerance as well as controlling the intensity of T cell effector responses.

Involvement of PD-1 in regulating T cell tolerance and autoimmunity was first suggested by the autoimmune phenotype of Pdcd1–/– mice18,29. PD-1 deficiency results in the development of a spontaneous, late-onset lupus-like disease and a dilated cardiomyopathy characterized by auto-antibodies to troponin-1 in C57BL/6 and BALB/c mice, respectively. Studies of mouse models of autoimmunity also emphasize important immunoregulatory functions for PD-1 and its ligands. In the nonobese diabetic (NOD) mouse model of diabetes, loss of PD-1 or PD-L1 but not of PD-L2 leads to rapid and exacerbated diabetes and more CD4+ and CD8+ T cells producing IFN-γ and tumor necrosis factor 20,38. PD-L1 is expressed on pancreatic islet cells as well as APCs, and PD-1-expressing cells are present in islets of mice with insulitis. Bone marrow–chimera experiments indicate that expression of PD-L1 on nonhematopoietic cells is critical for the control of self-reactive T cells20. The expression of PD-L1 on islet and endothelial cells suggests that T cells expressing PD-1 may productively interact with nonclassical APCs. Administration of anti-PD-1 or anti-PD-L1 to 1- to 10-week-old prediabetic NOD female and male mice leads to the rapid onset of diabetes and is associated with more IFN-γ-producing splenic T cells that recognize an islet antigen39. In a new model of antigen-specific therapy in which the administration of antigen-coupled fixed splenocytes induces tolerance and reverses dia-betes in NOD mice, PD-1–PD-L1 interactions are needed for both the induction and the maintenance of peripheral CD4+ T cell tolerance40. An intact PD-1–PD-L1 pathway is also required for the induction and maintenance of anti-CD3-induced tolerance. Notably, blockade of PD-1 or PD-L1 reverses anergy in islet antigen–specific T cells, whereas CTLA-4 blockade does not break anergy, indicating a unique function for PD-1–PD-L1 interactions in maintaining T cell anergy. Collectively, such studies demonstrate that PD-1–PD-L1 interactions regulate both the initiation and progression of autoimmune diabetes in NOD mice and identify PD-L1 as a key mediator of T cell tolerance in tissues, shielding target organs from diabetogenic effector T cells.

PD-1 and its ligands also suppress EAE19,41,42. PD-L1 is expressed on vascular endothelial cells, astrocytes and microglia, whereas PD-L2 is not found on resident brain cells. The administration of anti-PD-1 during the induction of EAE accelerates the onset and increases the severity of EAE and leads to increased frequency of IFN-γ-producing MOG-reactive

T cells and more MOG-specific antibodies in serum. Histological examination of the spinal cords of mice treated with anti-PD-1 shows greatly increased infiltration of CD4+ cells and an even greater increase in CD8+ T cells. Anti-PD-L2 but not anti-PD-L1 accelerates and worsens MOG-induced EAE in wild-type C57BL/6 mice. Severe EAE develops after immunization of 129/Sv PD-L1-deficient mice with MOG peptide (amino acids 35–55) or after the adoptive transfer of T cells specific for MOG peptide (amino acids 35–55) into 129/Sv PD-L1-deficient recipi-ent mice19. Transfer of wild-type or PD-L1-deficient encephalitogenic T cells into PD-L1-deficient recipient mice emphasizes a critical function for PD-L1 in limiting pathogenic effector T cell responses and shows that PD-L1 molecules both on the T cell and in the recipient restrain encephalitogenic T cell responses. The contrasting effects in anti-PD-L1–treated C57BL/6 mice and PD-L1-deficient 129/Sv mice may reflect differences in the timing of PD-L1 blockade or elimination. However, studies suggest both anti-PD-L1 and anti-PD-L2 can exacerbate EAE on other genetic backgrounds42, but such differences in disease induction do not correlate with altered amounts of PD-L1 or PD-L2 on traditional APCs.

Other microenvironments also seem to use PD-L proteins to gener-ate and maintain tolerance. It has been shown that PD-L2 is important in oral tolerance, with both CD4+ and CD8+ T cells failing to induce tolerance in PD-L2-deficient mice fed ovalbumin43. Expression of PD-L1 on parenchymal cells as well as APCs may protect mucosal tissues from self-reactive lymphocytes. Further studies are needed to determine whether the PD-1–PD-L pathway regulates deletion and/or regulatory T cell function as well as T cell anergy.

Studies of humans with autoimmune diseases also suggest important regulatory functions for PD-1 and its ligands. Although there is low expression of PD-L1 on unstimulated human monocytes, its expression is strongly upregulated by IFN-β and leads to reduced APC function in vitro44. Monocytes from healthy and untreated patients with multiple sclerosis have similar quantities and inducibility of PD-L1 on mono-cytes, Patients with multiple sclerosis treated with IFN-β in vivo for 6 months have eightfold more PD-L1 mRNA transcripts than before treat-ment. These results suggest that part of the anti-inflammatory effect of IFN-β treatment is due to PD-L1 expression44. Autoantibodies to PD-L1 have been found in patients with rheumatoid arthritis and correlate with active disease45. Such findings suggest that autoantibodies that block the inhibitory function of the PD-1–PD-L pathway may contribute to the development of autoimmune disease and that therapies that increase the expression of PD-L may ameliorate autoimmune disease.

PD-1–PD-L interactions in infectious diseaseThe PD-1–PD-L pathway is central in the interaction between host defenses aimed at eradicating pathogenic microbes and microbial strat-egies that evolved to resist immune responses. Many microorganisms that cause chronic infection exploit the PD-1–PD-L pathway to evade host immune effector mechanisms. Several studies suggest that the PD-1–PD-L pathway may regulate immune-mediated tissue damage during viral infection. In a mouse model of liver infection, PD-1 expression oscillates in association with T cell function in a way consistent with involvement of PD-1 in limiting tissue damage46. Pdcd1–/– mice clear adenovirus infection more rapidly but develop more severe hepatocel-lular injury than do wild-type mice47. Such studies suggest that the PD-1–PD-L pathway limits the damage caused by overaggressive T cells and may influence antiviral immunity in some conditions.

After an acute infection or vaccination, effective antiviral T cells acquire the ability to accomplish multiple effector functions (includ-ing cytokine production, perforin- and granzyme-mediated cytotox-icity and proliferation) after antigen encounter. Memory T cells gain

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the ability to persist in an antigen-independent way through IL-7- and IL-15-driven homeostatic proliferation48–50. Chronic viral infections, in contrast, are often characterized by T cell dysfunction. For example, during chronic LCMV infection, virus-specific CD8+ T cells lose the ability to produce cytokines, lyse infected cells and proliferate in a pro-gressive and hierarchical way50,51. Less-exhausted T cells respond more effectively to therapeutic vaccination49 and, in humans, preservation of multifunctional T cells (less exhaustion) corresponds to prolonged control of human immunodeficiency virus (HIV) infection52,53. Such T cell ‘exhaustion’ has been noted during many types of chronic viral infection in animal models and in humans49,50,54. Although the precise functional defects often differ, the general idea of T cell dysfunction seems to be a common feature of persistent infection, probably criti-cal for preventing overt immunopathology but perhaps detrimental to optimal antiviral immunity.

The PD-1–PD-L pathway contributes directly to T cell dysfunction and lack of viral control in established chronic infection (Fig. 2). In mice, PD-1 expression on virus-specific CD8+ T cells increases during the first week of LCMV infection, consistent with the upregulation of PD-1 on activated T cells12. If the infection is cleared, PD-1 expres-sion quickly decreases and functional memory T cells are generated. In contrast, if mice are infected with the LCMV clone 13 strain that causes chronic infection, PD-1 expression remains higher and T cell function decreases. In addition, PD-L1 on splenocytes increases during chronic LCMV infection, with the most PD-L1 on virus-infected cells. In vivo blockade of PD-1–PD-L1 interactions in chronically infected mice restores T cell function and leads to enhanced viral control12. Studies of PD-L1-deficient mice infected with LCMV clone 13 also indicate involvement of PD-L1 in limiting immunopathology; wild-type mice develop a chronic infection, whereas PD-L1-deficient mice die12.

Those observations also apply to humans; several groups have dem-onstrated that PD-1 expression is higher on HIV-specific T cells55–57, HBV-specific T cells58 and HCV-specific T cells59. In contrast, T cells specific for nonpersisting viruses such as vaccinia55,56 or influenza59 have low PD-1 expression55–57,59. Blocking PD-1–PD-L interactions in vitro reverses the exhaustion of HIV- and HCV-specific CD8+ and CD4+ T cells and restores cytokine production and proliferation55–57,59. In some people, HIV-specific CD4+ T cell responses are detected only when the PD-1–PD-L pathway is blocked55. Notably, PD-1 expression

on virus-specific CD8+ T cells decreases in people who have resolved HCV infection but remains high in patients who progress to chronic HCV infection59. A similar decrease in PD-1 expression on HBV-specific CD8+ T cells has also been reported in people who control infection58. PD-L1 and PD-L2 expression has also been examined in the livers of HCV-infected people. Normally hepatocytes have low expression of PD-L1, but its expression is substantially upregulated by viral infection and by type 1 and type 2 interferons10. These observations from both animal models and human studies indicate that PD-1 expression on virus-specific T cells may limit antiviral effectiveness by downregulating function and proliferation.

Many other viruses may use the PD-1–PD-L pathway as a strategy for evading the immune system and/or limiting immune-mediated host tis-sue damage. Human rhinovirus, a chief cause of the common cold, can blunt immune responses in the respiratory tract, which may predispose to secondary bacterial infections. Human rhinovirus 14 downregulates the T cell stimulatory function of DCs. Binding of this virus to DCs induces the expression of PD-L1 and sialoadhesion on human DCs, and blockade of PD-L1 restores the T cell stimulatory function of the DCs in vitro, suggesting that PD-L1 may mediate, in part, the immuno-modulatory effects of human rhinovirus60. In a mouse model of herpes stromal keratitis, PD-L1 expression is upregulated on CD11b+ mac-rophages and PD-1 is upregulated on CD4+ T cells in draining lymph nodes and inflamed corneas after infection61. Administration of PD-L1-specific blocking antibody leads to exacerbated keratitis and increased HSV-1-specific effector CD4+ T cell proliferation, IFN-γ production and survival, suggesting that PD-L1 may limit immune-mediated tis-sue damage in herpes stromal keratitis infection61. Notably, infection with respiratory syncytial virus upregulates the expression of PD-L1 and PD-L2 on human tracheal, bronchial and alveolar cell lines62. At least one group has found defects in respiratory syncytial virus–specific T cell functions during infection in mice63. Further studies are needed to investigate whether the PD-1–PD-L pathway is directly involved in the failure to develop respiratory syncytial virus–specific memory immune responses.

Persistent infection with pathogens other than viruses may also be associated with suboptimal T cell responsiveness. Helicobacter pylori leads to chronic infection, gastroduodenal ulcers and gastric cancer. Many reports have described impaired T cell responses during H. pylori

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Figure 2 The PD-1–PD-L pathway contributes directly to T cell dysfunction and lack of viral control during chronic viral infection. Activated antigen-bearing APCs have higher expression of CD80 and CD86 and stimulate the proliferation, cytokine production and cytotoxic activity of antigen-specific naive T cells. During chronic infection or in the presence of persisting antigen, T cells become ‘exhausted’ and lose the ability to proliferate. Exhausted T cells have high expression of PD-1 and receive a strong coinhibitory signal when engaging PD-L-expressing APCs. Blockade of interactions between PD-1 and its ligands can ‘reinvigorate’ T cells to expand their populations and regain effector functions, including cytokine production and cytolysis. Interactions of costimulatory receptor (Constim-R) with costimulatory ligand (Costim-L) might include pathways in the B7-CD28, tumor necrosis factor–tumor necrosis factor receptor and CD2 families. MHC, major histocompatibility complex.

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infection64–66. Gastric epithelial cells constitutively express major his-tocompatibility complex class II molecules and are thought to have an important function as APCs during H. pylori infection. Studies have shown that PD-L1 is upregulated on human gastric epithelial cell lines by H. pylori infection and that anti-PD-L1 enhances T cell proliferation and IL-2 production66. PD-L1 is upregulated in gastric biopsies from people infected with H. pylori compared with samples from uninfected people, suggesting involvement of PD-L1 on the epithelium in promoting per-sistence of infection. Similarly, repeated exposure to lipopolysaccharide from Porphyromonas gingivalis, a chief cause of human periodontal dis-ease, can induce tolerogenic monocytes with high expression of PD-L1 and lower expression of CD80 and CD86 costimulatory molecules67.

Persisting infection with mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium leprae, may also be associated with lower T cell proliferation and altered cytokine produc-tion68,69. Altered or suppressed T cell responses have also been reported during other persistent bacterial infections, including Chlamydia tra-chomatis70. Although many regulatory pathways may contribute to the persistence of intracellular bacteria, it will be useful to determine the function of the PD-1–PD-L pathway in such settings.

Parasitic worms also exploit the PD-1–PD-L pathway to induce acti-vated macrophages with strong suppressive activity (Fig. 3). During Schistosoma mansoni infection in mice, T cell anergy develops and is mediated by macrophages. Splenic macrophages have high expression of PD-L1 and more modest expression of PD-L2. Anti-PD-L1 ablates the ability of such macrophages to suppress T cell proliferation in vitro, whereas anti-PD-L2 has no effect. Expression of PD-L1 on macrophages from infected mice decreases after 12 weeks of infection, correlating with the break in T cell anergy71. Similarly, PD-1–PD-L interactions mediate the suppressive effects of macrophages induced during Taenia crassiceps infection in mice. PD-L1 and PD-L2 are upregulated on acti-vated macrophages, and a high percentage of CD4+ T cells express PD-1 in mice infected with T. crassiceps. Blockade of PD-L1, PD-L2 or PD-1

substantially reduces the suppression of T cell proliferation by T. crassi-ceps–induced macrophages in vitro72.

PD-L1 and PD-L2 have distinct functions in regulating the immune response to the protozoan parasite Leishmania mexicana73. PD-L1-deficient mice have lower parasite burdens and lesion development, whereas PD-L2-deficient mice develop exacerbated disease with higher para-site burdens. PD-L1-deficient mice have an inadequate T helper type 2 response, which may explain the greater resistance of PD-L1-deficient mice. PD-L2-deficient mice have much more L. mexicana–specific IgM and IgG2a. Higher L. mexicana–specific IgG production may suppress the healing response through ligation of Fcγ receptors on macrophages. Further studies are needed to understand whether the distinct outcomes of infection reflect impaired PD-1 signaling into T cells, B cells and/or macrophages.

PD-1 polymorphisms and human diseasePolymorphisms in PDCD1 have been associated with several autoim-mune diseases, including systemic lupus erythematosis (SLE), type 1 diabetes, rheumatoid arthritis and multiple sclerosis, suggesting a key function for this pathway in the pathogenesis of human autoimmune diseases74–83. An intronic single-nucleotide polymorphism in PDCD1 is associated with the development of SLE in Swedish, European-American and Mexican patients78, an increased risk for type 1 diabetes in Danish patients76, rheumatoid arthritis in European patients who are negative for rheumatoid factor81, and a progressive course of multiple sclerosis in German patients74. This single-nucleotide polymorphism (G7146A) is located in a binding site for the transcription factor Runx1 (also called AML-1), which is thought to have a key regulatory function in hema-topoiesis. Disruption of the Runx1-binding site may alter the amount or stability of PDCD1 mRNA. PD-1-mediated inhibition of IFN-γ pro-duction is impaired in German patients with multiple sclerosis who have the G7146A polymorphism74. In a study of a Spanish population, an association of PD-1 with susceptibility to SLE was confirmed but was not associated with the G7146A single-nucleotide polymorphism84; variation in haplotype structures in different populations could account for the observed differences79. Single-nucleotide polymorphisms other than G7146A are associated with rheumatoid arthritis in the Chinese population77, SLE (but not rheumatoid arthritis) in a Chinese popula-tion in Taiwan82, lupus nephropathy in Caucasian SLE patients80, anky-losing spondylitis in a Korean population83, and specific IgE response to grass allergens in atopic people85. Most of these mutations are found in conserved regions in intronic sequences.

Links among infection, tolerance and autoimmunityThe PD-1–PD-L pathway has a distinct function in regulating self toler-ance and autoimmunity. It also seems that pathogens exploit this inhibi-tory pathway to downregulate T cell responses and facilitate pathogen persistence. It will be useful to further understand how the PD-1–PD-L pathway regulates that balance among tolerance, autoimmunity, infec-tion and immunopathology.

Further work is needed to understand how and when the PD-1–PD-L pathway most effectively exerts its inhibitory effects. T cell activation is a summation of positive and negative signals specified by the expres-sion of ligands and receptors on T cells and APCs. A negative signal in the absence of a positive signal can be tolerogenic. Conversely, strong positive signals can override negative signals. There are many situations in which PD-1 and its ligands are expressed, but the pathway does not inhibit T cell responses. Growth factors such as IL-2 can overcome the inhibitory effects of PD-1 in vitro. PD-1 seems to be most effective in limiting responses in situations involving low-affinity TCRs or weakly activated T cells (such as exhausted T cells).

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Figure 3 Infection with parasites can upregulate PD-L on macrophages that induce T cell anergy. Some microbes exploit the PD-1–PD-L pathway by stimulating expression of PD-L1 and/or PD-L2 on macrophages. Infection with the helminthes, S. mansoni or T. crassiceps stimulates the expression of PD-L on activated macrophages. Such macrophages have strong suppressive activity and induce T cell anergy.

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Several pathogens have been associated with autoimmunity86–90. The PD-1–PD-L pathway may be of particular interest to examine during such infections. For example, chronic infection with the Lyme disease pathogen Borrelia burgdorferi often results in autoimmune arthritis86. Although molecular mimicry is one potential explanation for pathogen-associated autoimmunity, other mechanisms also probably influence self-reactivity during microbial infections. It is notable that most of these situations are persistent infections in which negative regulatory path-ways such as PD-1–PD-L may be used to prevent immunopathology. Using such a negative regulatory pathway may provide the opportunity for dysregulation of self-reactive B and T cells. Studies are needed to determine whether modulation of the PD-1–PD-L1 pathway during persistent infection affects the balance between pathogen control and pathogen-associated autoimmunity. Also, many PDCD1 polymorphisms have been associated with autoimmune diseases in humans. Such poly-morphisms may have been selected during evolution to enable host survival after infection. Further studies are needed to determine whether the PDCD1 locus is associated with resistance to infectious diseases. The therapeutic potential of manipulation of the PD-1–PD-L pathway by antagonists to enhance immune responses during chronic infection or by agonists to limit autoreactive immune responses gives impetus to fur-ther investigation of the functions of PD-1 and its ligands in modulating antimicrobial immunity, autoimmunity and immunopathology.

ACKNOWLEDGMENTSSupported by the National Institutes of Health, the National Multiple Sclerosis Society and the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative.

COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests.

Published online at http://www.nature.com/natureimmunology/Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions

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