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Role of the PD-1 Pathway in the Immune Response
Open accessAbstract
Understanding immunoregulatory mechanisms is essential for the development of novel interventions to improve long-term allograft survival. Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, have emerged as critical inhibitory signaling pathways that regulate T cell response and maintain peripheral tolerance. PD-1 signaling inhibits alloreactive T cell activation, and can promote induced regulatory T cell development. Furthermore, the upregulation of PD-L1 on nonhematopoietic cells of the allograft may actively participate in the inhibition of immune responses and provide tissue-specific protection. In murine transplant models, this pathway has been shown to be critical for the induction and maintenance of graft tolerance. In this review, we discuss the current knowledge of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential in transplantation.
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“T cell proliferation and function can also be enhanced by blocking signalling through the inhibitory receptors such as PD-1 [77].”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [77]
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“and this is an important strategic point because the use of PD-1/PD-L1 therapy has been reported to impair Treg cells in the renal allograft.173”
From Autoimmune diseases and immune-checkpoint inhibitors for cancer therapy: Review of the literature and personalized risk-based prevention strategy (2020) · cites this paper as [173]
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Cites
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BackgroundPD-L1 regulates the development, maintenance, and function of induced regulatory T cells
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BackgroundInfluentialSelf-citationCTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms
Parry, R. V., Chemnitz, J. M., Frauwirth, K. A., Lanfranco, A. R., Braunstein, I., Kobayashi, S. V., Linsley, P. S., Thompson, C. B., & Riley, J. L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9543-9553.2005 · Cited by 1,931 · cited 3×
“Phosphorylation of the ITSM motif leads to the recruitment of SH2-domain containing tyrosine phosphatase 2 (SHP-2), and possibly SHP-1, to the cytoplasmic domain of PD-1, which then down-regulates CD28-mediated PI3K activity and consequently, leads to less activation of Akt (Figure 1) (35).”
BackgroundInfluentialAutoimmune Dilated Cardiomyopathy in PD-1 Receptor-Deficient Mice
Nishimura, H., Okazaki, T., Tanaka, Y., Nakatani, K., Hara, M., Matsumori, A., Sasayama, S., Mizoguchi, A., Hiai, H., Minato, N., et al. (2001) · Science · doi:10.1126/science.291.5502.319 · Cited by 1,868 · cited 1×
“PD-1−/− and PDL1−/− NOD mice develop accelerated spontaneous diabetes, which manifests in 100% of male and female mice by 10 weeks (36,54).”
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BackgroundInfluentialSelf-citationExpression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes
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Wherry, E. J., Ha, S., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.11.006 · Cited by 1,355
Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity
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“including melanoma, renal cell carcinoma, colorectal cancer and nonsmall cell lung cancer as well as in hematologic malignancies [reviewed in (126)].”
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“PD-1 can also inhibit T cell proliferation (5,36), and inhibit the upregulation of Bcl-xL, an antiapoptotic protein (33).”
BackgroundTissue expression of PD-L1 mediates peripheral T cell tolerance
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“PD-1−/− and PDL1−/− NOD mice develop accelerated spontaneous diabetes, which manifests in 100% of male and female mice by 10 weeks (36,54).”
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Kretschmer, K., Apostolou, I., Hawiger, D., Khazaie, K., Nussenzweig, M. C., & von Boehmer, H. (2005) · Nature Immunology · doi:10.1038/ni1265 · Cited by 1,240
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BackgroundRedefining Chronic Viral Infection
Virgin, H. W., Wherry, E. J., & Ahmed, R. (2009) · Cell · doi:10.1016/j.cell.2009.06.036 · Cited by 1,031 · cited 1×
“PD-1 is highly expressed on “exhausted” T cells that develop during chronic viral infections in animals and humans (122).”
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“While PD-1 upregulation on naı̈ve T cells peaks at 48 h after anti-CD3 or anti-CD3/anti-CD28 stimulation in vitro (12), PD-1 on allogeneic CD4+ T cells progressively increases over time following skin transplantation in vivo, reaching the highest levels on day 10 posttransplant (13).”
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B7-Dc, a New Dendritic Cell Molecule with Potent Costimulatory Properties for T Cells
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“PD-1 has two ligands, PD-L1 (B7H1; CD274) (4) and PD-L2 (B7-DC; CD273) (5,6), both of which have Ig-V-like and Ig-C-like extracellular domains and a short intracellular domain.”
BackgroundT cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR
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Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero
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BackgroundThe Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice
Ansari, M. J., Salama, A. D., Chitnis, T., Smith, R. N., Yagita∥, H., Akiba, H., Yamazaki, T., Azuma, M., Iwai, H., Khoury, S. J., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20022125 · Cited by 817
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BackgroundInteractions between PD-1 and PD-L1 promote tolerance by blocking the TCR–induced stop signal
Fife, B. T., Pauken, K. E., Eagar, T. N., Kangas, T. O., Wu, J. Q., Tang, Q., Azuma, M., Krummel, M. F., & Bluestone, J. A. (2009) · Nature Immunology · doi:10.1038/ni.1790 · Cited by 759 · cited 1×
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BackgroundIn Vivo Instruction of Suppressor Commitment in Naive T Cells
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TGF-β Suppresses Tumor Progression in Colon Cancer by Inhibition of IL-6 trans-Signaling
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“However, as discussed earlier in this review, the precise role of the PD-1 pathway in regulating T cell-dependent antibody responses is still unclear (42,43).”
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“In light of the increased awareness of donor-specific alloantibodies as contributors to chronic rejection, interest in TFH in alloimmune responses has expanded.”
BackgroundInfluentialRegulation of PD‐1, PD‐L1, and PD‐L2 expression during normal and autoimmune responses
Liang, S. C., Latchman, Y. E., Buhlmann, J. E., Tomczak, M. F., Horwitz, B. H., Freeman, G. J., & Sharpe, A. H. (2003) · European Journal of Immunology · doi:10.1002/eji.200324228 · Cited by 649 · cited 1×
“In addition, it can be upregulated on nonhematopoietic cells, including vascular endothelial cells, epithelial cells, muscle cells, hepatocytes, placental cells and pancreatic islet cells (19,20).”
BackgroundSelf-citationFollicular B helper T cells in antibody responses and autoimmunity
Vinuesa, C. G., Tangye, S. G., Moser, B., & Mackay, C. R. (2005) · Nature reviews. Immunology · doi:10.1038/nri1714 · Cited by 646 · cited 2×
“Among T cells, TFH have emerged as key supporters of the B cell response (40).”
BackgroundPD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells
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“IL-4 and GM CSF are the strongest known stimuli for inducing PD-L2 expression (5,12,19,23,24).”
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“PD-L1 engagement of its receptors (PD-1, and possibly B7–1) on naı̈ve T cells leads to iTreg development, at least in part, by inhibiting mTOR/Akt signaling, as shown by experiments using microbeads coated with anti-CD3, anti-CD28 and PD-L1 fusion protein as artificial APCs (77).”
BackgroundResultInfluentialSelf-citationResting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4
Probst, H. C., McCoy, K. D., Okazaki, T., Honjo, T., & van den Broek, M. F. (2005) · Nature Immunology · doi:10.1038/ni1165 · Cited by 568 · cited 1×
“PD-1 deficiency on self antigen-specific T cells increases CD8 T cell responses to antigen-bearing resting DCs, and abrogates CD8 T cell tolerance to peripheral self-antigen expression in vivo (30,31,61).”
BackgroundCutting Edge: IL-2 Is Essential for TGF-β-Mediated Induction of Foxp3+ T Regulatory Cells
Davidson, T. S., DiPaolo, R. J., Andersson, J., & Shevach, E. M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.7.4022 · Cited by 521
Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes
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“Regulatory T cells Regulatory T cell populations are critical for the maintenance of peripheral tolerance, are potent inhibitors of many immune responses and play an important role in the prevention of graft rejection (64,65).”
BackgroundKinter, A. L., Godbout, E. J., McNally, J. P., Sereti, I., Roby, G. A., O’Shea, M. A., & Fauci, A. S. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.10.6738 · Cited by 513 · cited 1×
“The common c -chain cytokines (IL-2, IL-7, IL-15 and IL-21), TLRs and interferons also can potentiate PD-1 expression on T cells (10).”
BackgroundSalama, A. D., Chitnis, T., Imitola, J., Ansari, M. J., Akiba, H., Tushima, F., Azuma, M., Yagita∥, H., Sayegh, M. H., & Khoury, S. J. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20022119 · Cited by 506
Endothelial expression of PD‐L1 and PD‐L2 down‐regulates CD8+ T cell activation and cytolysis
Rodig, N., Ryan, T., Allen, J. A., Pang, H. B., Grabie, N., Chernova, T., Greenfield, E. A., Liang, S. C., Sharpe, A. H., Lichtman, A. H., et al. (2003) · European Journal of Immunology · doi:10.1002/eji.200324270 · Cited by 503 · cited 2×
“In the setting of IFN-c and/or allostimulation, the endothelium is known to upregulate PD-L1 (19,32,116).”
BackgroundSelf-citationSaid, E. A., Dupuy, F. P., Trautmann, L., Zhang, Y., Shi, Y., Far, M. E., Hill, B. J., Noto, A., Ancuța, P., Peretz, Y., et al. (2010) · Nature Medicine · doi:10.1038/nm.2106 · Cited by 490
The PDL1-PD1 Axis Converts Human T H 1 Cells into Regulatory T Cells
Amarnath, S., Mangus, C. W., Wang, J. C. M., Wei, F., He, A., Kapoor, V., Foley, J., Massey, P. R., Felizardo, T. C., Riley, J. L., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3003130 · Cited by 463 · cited 2×
“showed that PD-L1:PD-1 signaling was critical for the conversion of human Th1 cells into Tregs in vivo, preventing the development of xGVHD (81).”
BackgroundThe Inhibitory Receptor PD-1 Regulates IgA Selection and Bacterial Composition in the Gut
Kawamoto, S., Tran, T. H., Maruya, M., Suzuki, K., Doi, Y., Tsutsui, Y., Kato, L. M., & Fagarasan, S. (2012) · Science · doi:10.1126/science.1217718 · Cited by 451 · cited 1×
“PD-1 deficiency can lead to generation of increased numbers of TFH cells with aberrant phenotypes that lead to dysregulated selection of B cells and antibody diversity in germinal centers (44).”
BackgroundEstablishment of NOD- Pdcd1 -/- mice as an efficient animal model of type I diabetes
Wang, J., Yoshida, T., Nakaki, F., Hiai, H., Okazaki, T., & Honjo, T. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505497102 · Cited by 450 · cited 1×
“However, susceptibility to autoimmune disease is exacerbated in PD-1−/− mice on an autoimmune-prone background (52,53).”
BackgroundA critical role for the programmed death ligand 1 in fetomaternal tolerance
Guleria, I., Khosroshahi, A., Ansari, M. J., Habicht, A., Azuma, M., Yagita∥, H., Noelle, R. J., Coyle, A. J., Mellor, A. L., Khoury, S. J., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050019 · Cited by 447 · cited 1×
“Interestingly, PD-L1 blockade or deficiency in B6 females mated with male allogeneic CBA mice results in decreased allogeneic fetal survival rates (113).”
BackgroundNFATc1 Regulates PD-1 Expression upon T Cell Activation
Oestreich, K. J., Yoon, H., Ahmed, R., & Boss, J. M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.7.4832 · Cited by 416 · cited 1×
“Expression of PD-1 is in part mediated by the recruitment of the nuclear factor of activated T cells c1 (NFATc1) to the nucleus (11).”
BackgroundReinvigorating exhausted HIV-specific T cells via PD-1–PD-1 ligand blockade
Freeman, G. J., Wherry, E. J., Ahmed, R., & Sharpe, A. H. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061800 · Cited by 406 · cited 1×
“PD1 is upregulated after TCR or BCR engagement on naı̈ve lymphocytes and persistent antigen stimulation maintains high PD-1 expression (9).”
BackgroundSelf-citationWang, L., Pino‐Lagos, K., de Vries, V. C., Guleria, I., Sayegh, M. H., & Noelle, R. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710441105 · Cited by 405 · cited 1×
“PDL1−/− DCs were shown to be defective at supporting the TGFb-induced conversion of naı̈ve T cells to Tregs in vitro, and conversion and maintenance of iTreg function in vivo was also dependent on PD-L1 (79).”
BackgroundB7-H1 Determines Accumulation and Deletion of Intrahepatic CD8+ T Lymphocytes
Dong, H., Zhu, G., Tamada, K., Flies, D. B., van Deursen, J. M. A., & Chen, L. (2004) · Immunity · doi:10.1016/s1074-7613(04)00050-0 · Cited by 375
Deenick, E. K., Chan, A., Ma, C. S., Gatto, D., Schwartzberg, P. L., Brink, R. A., & Tangye, S. G. (2010) · Immunity · doi:10.1016/j.immuni.2010.07.015 · Cited by 354 · cited 1×
“TFH cells provide B cell help necessary for the generation of an effective antibody-mediated response (40) and express high amounts of PD-1 (CD44+CXCR5highPD-1high) (104).”
Strauss, L., Whiteside, T. L., Knights, A. J., Bergmann, C., Knuth, A. K., & Zippelius, A. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.1.320 · Cited by 339
Blazar, B. R., Carreno, B. M., Panoskaltsis‐Mortari, A., Carter, L., Iwai, Y., Yagita∥, H., Nishimura, H., & Taylor, P. A. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.3.1272 · Cited by 332 · cited 6×
“The accelerated GVHD was dependent on IFN-c , and additional blockade of CTLA-4 further hastened the disease, supporting a nonredundant role of CTLA-4 and PD-1 in GVHD (105).”
BackgroundInfluentialB7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance
Park, J., Omiya, R., Matsumura, Y., Sakoda, Y., Kuramasu, A., Augustine, M. M., Yao, S., Tsushima, F., Narazaki, H., Anand, S., et al. (2010) · Blood · doi:10.1182/blood-2010-01-265975 · Cited by 331 · cited 1×
“A similar predominant direction of signaling was observed in a model of tolerance, in which OVA-reactive OT-I T cells undergo activation in response to injection of high-dose OVA257–264 peptide (107).”
BackgroundInsulin-induced remission in new-onset NOD mice is maintained by the PD-1–PD-L1 pathway
Fife, B. T., Guleria, I., Bupp, M. G., Eagar, T. N., Tang, Q., Bour-Jordan, H., Yagita∥, H., Azuma, M., Sayegh, M. H., & Bluestone, J. A. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061577 · Cited by 331 · cited 1×
“For example, the PD-1 pathway is a critical mediator of tolerance induced by administration of antigen-coupled fixed splenocytes, which can reverse diabetes in NOD mice (60).”
BackgroundEngagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease
Paust, S., Lu, L., McCarty, N., & Cantor, H. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403342101 · Cited by 328 · cited 1×
“A function for B7–1 on T cells has been suggested previously (108).”
BackgroundB cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells
Lee, S. K., Rigby, R. J., Zotos, D., Tsai, L. M., Kawamoto, S., Marshall, J. L., Ramiscal, R. R., Chan, T. D., Gatto, D., Brink, R. A., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20102065 · Cited by 327 · cited 1×
“TFH express high levels of PD-1 (15,41), and PD-L1 and PD-L2 are upregulated on germinal center B cells (42).”
BackgroundTGFβ signalling in control of T-cell-mediated self-reactivity
Rubtsov, Y. P., & Rudensky, A. Y. (2007) · Nature reviews. Immunology · doi:10.1038/nri2095 · Cited by 317
Franceschini, D., Paroli, M., Francavilla, V., Videtta, M., Morrone, S., Labbadia, G., Cerino, A., Mondelli, M. U., & Barnaba, V. (2009) · Journal of Clinical Investigation · doi:10.1172/jci36604 · Cited by 316 · cited 2×
“Antibody blockade studies suggest that this pathway inhibits expansion of established Tregs, as well as effector T cells (89,90).”
BackgroundZhou, Q., Munger, M. E., Highfill, S. L., Tolar, J., Weigel, B. J., Riddle, M. J., Sharpe, A. H., Vallera, D. A., Azuma, M., Levine, B. L., et al. (2010) · Blood · doi:10.1182/blood-2010-03-275446 · Cited by 294 · cited 1×
“Furthermore, in a model of acute myeloid leukemia, adoptively transferred AML-reactive cytotoxic T cells were more effective at eradicating the tumor after PD-L1 blockade (106).”
BackgroundSelf-citationWang, S., Bajorath, J., Flies, D. B., Dong, H., Honjo, T., & Chen, L. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20021752 · Cited by 294 · cited 1×
“There are data to suggest that PD-L2 may have another receptor, the identity of which is still unknown (26).”
BackgroundEndothelial Programmed Death-1 Ligand 1 (PD-L1) Regulates CD8 + T-Cell–Mediated Injury in the Heart
Grabie, N., Gotsman, I., DaCosta, R., Pang, H. B., Stavrakis, G., Butte, M. J., Keir, M. E., Freeman, G. J., Sharpe, A. H., & Lichtman, A. H. (2007) · Circulation · doi:10.1161/circulationaha.107.709360 · Cited by 291 · cited 1×
“Indeed, nonhematopoietic expression of PD-L1 contributes to prevention of diabetes in the NOD mouse model (36) and regulates self-reactive CD8+ T cell responses in other models of self-tolerance (30,115).”
BackgroundSelf-citationPD-1 Protects against Inflammation and Myocyte Damage in T Cell-Mediated Myocarditis
Tarrio, M. L., Grabie, N., Bu, D.-X., Sharpe, A. H., & Lichtman, A. H. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200389 · Cited by 288 · cited 1×
“PD-1 deficiency on self antigen-specific T cells increases CD8 T cell responses to antigen-bearing resting DCs, and abrogates CD8 T cell tolerance to peripheral self-antigen expression in vivo (30,31,61).”
BackgroundSelf-citationSchreiner, B., Mitsdoerffer, M., Kieseier, B. C., Chen, L., Hartung, H.-P., Weller, M., & Wiendl, H. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.06.013 · Cited by 276 · cited 1×
“IL-4 and GM CSF are the strongest known stimuli for inducing PD-L2 expression (5,12,19,23,24).”
BackgroundExpression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells
Eppihimer, M., Gunn, J., Freeman, G., Greenfield, E., Chernova, T., Erickson, J., & Leonard, J. (2002) · Microcirculation · doi:10.1080/713774061 · Cited by 272
Selenko-Gebauer, N., Majdic, O., Szekeres, A., Höfler, G., Guthann, E., Korthäuer, U., Zlabinger, G. J., Steinberger, P., Pickl, W. F., Stockinger, H. S. J., et al. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.7.3637 · Cited by 265 · cited 1×
“For example, PD-L1 expression is high in tolerogenic subsets of DCs, Tregs and mesenchymal stem cells (32,100,101), whereas the expression of PD-L2 is mostly restricted to professional APCs.”
BackgroundT‐cell tolerance or function is determined by combinatorial costimulatory signals
Nurieva, R., Thomas, S., Nguyen, T. D., Martín‐Orozco, N., Wang, Y., Murali‐Krishna, K., Yu, X., & Dong, C. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601146 · Cited by 250 · cited 2×
“However, a strong positive signaling through CD28 and/or IL-2 receptor can overcome PD-1 inhibitory effects on T cell proliferation, differentiation and survival (5,18,37,38).”
BackgroundProgrammed Death-1 Targeting Can Promote Allograft Survival
Özkaynak, E., Wang, L., Goodearl, A. D. J., McDonald, K., Qin, S., O’Keefe, T. L., Duong, T., Smith, T., Gutierrez-Ramos, J.-C., Rottman, J. B., et al. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.11.6546 · Cited by 247
Duraiswamy, J., Ibegbu, C., Masopust, D., Miller, J. D., Araki, K., Doho, G., Tata, P., Sk, G., Zilliox, M. J., Nakaya, H. I., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1001783 · Cited by 246
PD-1 Regulates Self-Reactive CD8+ T Cell Responses to Antigen in Lymph Nodes and Tissues
Keir, M. E., Freeman, G. J., & Sharpe, A. H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.8.5064 · Cited by 243 · cited 2×
“Indeed, nonhematopoietic expression of PD-L1 contributes to prevention of diabetes in the NOD mouse model (36) and regulates self-reactive CD8+ T cell responses in other models of self-tolerance (30,115).”
BackgroundSelf-citationMaternal Acceptance of the Fetus: True Human Tolerance
Guleria, I., & Sayegh, M. H. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.6.3345 · Cited by 240 · cited 2×
“PD-L1 is highly expressed on Tregs and in trophoblasts lining the decidua layer of the placenta (111).”
BackgroundDejean, A. S., Beisner, D. R., Ch’en, I. L., Kerdiles, Y. M., Babour, A., Arden, K. C., Castrillón, D. H., DePinho, R. A., & Hedrick, S. Μ. (2009) · Nature Immunology · doi:10.1038/ni.1729 · Cited by 238 · cited 2×
“However, American Journal of Transplantation 2012; 12: 2575–2587 2581 there are some studies indicating that B7–1 may signal into DCs and lead to the upregulation of IDO (109,110).”
BackgroundPD-1 on dendritic cells impedes innate immunity against bacterial infection
Yao, S., Wang, S., Zhu, Y., Luo, L., Zhu, G., Flies, S. J., Xu, H., Ruff, W. E., Broadwater, M., Choi, I.-H., et al. (2009) · Blood · doi:10.1182/blood-2009-02-203141 · Cited by 217 · cited 1×
“Recently described roles for PD-1 expression on DCs and monocytes highlight the possibility that PD-1 signaling may also occur independently of T cell or B cell antigen receptor signaling, possibly by impinging on other receptor signaling pathways (45,46).”
BackgroundSo, T., & Croft, M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.3.1427 · Cited by 211
Tanaka, K., Albin, M. J., Yuan, X., Yamaura, K., Habicht, A., Murayama, T., Grimm, M. R., Waaga, A. M., Ueno, T., Padera, R. F., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.8.5204 · Cited by 208
Kuipers, H., Muskens, F., Willart, M. A. M., Hijdra, D., van Assema, F., Coyle, A. J., Hoogsteden, H. C., & Lambrecht, B. N. (2006) · European Journal of Immunology · doi:10.1002/eji.200635978 · Cited by 200 · cited 1×
“Data supporting PD-L1 and/or PDL2 signaling are primarily based on experiments using soluble PD-1 reagents that engage PD-L1/2 and lead to upregulation of IL-10 production and reduction in DC function (4,47).”
BackgroundCostimulatory pathways in transplantation: challenges and new developments
Li, X. C., Rothstein, D. M., & Sayegh, M. H. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00781.x · Cited by 199 · cited 1×
“Some costimulatory interactions potentiate the activation and proliferation of naı̈ve T cells, while others inhibit T cell activation and promote regulation (1,2).”
BackgroundNishimura, H., Honjo, T., & Minato, N. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.5.891 · Cited by 198
Lucas, J. A., Weinmann‐Menke, J., Rabacal, W., Schöen, F. J., Sharpe, A. H., & Kelley, V. R. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.4.2513 · Cited by 196
Self-citationZhong, X., Tumang, J. R., Gao, W., Bai, C., & Rothstein, T. L. (2007) · European Journal of Immunology · doi:10.1002/eji.200737461 · Cited by 193 · cited 1×
“PD-L2 is upregulated on DCs, macrophages, bone marrow-derived mast cells and on a subset of peritoneal B1 B cells as well as on germinal center B cells (21).”
BackgroundRole of the Programmed Death-1 Pathway in Regulation of Alloimmune Responses In Vivo
Sandner, S. E., Clarkson, M. R., Salama, A. D., Fueyo, A. S., Domenig, C. M., Habicht, A., Najafian, N., Yagita∥, H., Azuma, M., Turka, L. A., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.6.3408 · Cited by 190 · cited 4×
“While PD-1 upregulation on naı̈ve T cells peaks at 48 h after anti-CD3 or anti-CD3/anti-CD28 stimulation in vitro (12), PD-1 on allogeneic CD4+ T cells progressively increases over time following skin transplantation in vivo, reaching the highest levels on day 10 posttransplant (13).”
BackgroundMethodInfluentialThe Link between the PDL1 Costimulatory Pathway and Th17 in Fetomaternal Tolerance
D’Addio, F., Riella, L. V., Mfarrej, B. G., Chabtini, L., Adams, L. T., Yeung, M. Y., Yagita∥, H., Azuma, M., Sayegh, M. H., & Guleria, I. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002031 · Cited by 172
Self-citationRegulation of T cell activation and tolerance by PDL2
Zhang, Y., Chung, Y., Bishop, C., Daugherty, B., Chute, H. T., Holst, P. L., Kurahara, C., Lott, F. D., Sun, N., Welcher, A. A., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601347103 · Cited by 163 · cited 1×
“PD-L2 is required for oral tolerance, as shown by failure of oral tolerance in PD-L2−/− mice (62).”
BackgroundGao, W., Demirci, G., Strom, T. B., & Li, X. C. (2003) · Transplantation · doi:10.1097/01.tp.0000085010.39567.fb · Cited by 159 · cited 2×
“Similarly, PD-L1-Ig prevented islet allograft rejection and facilitated tolerance induction when combined with anti-CD154 or suboptimal doses of rapamycin (118).”
BackgroundKrupnick, A. S., Gelman, A. E., Barchet, W., Richardson, S., Kreisel, F. H. C., Turka, L. A., Colonna, M., Patterson, G. A., & Kreisel, D. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.10.6265 · Cited by 157
Keir, M. E., Latchman, Y. E., Freeman, G. J., & Sharpe, A. H. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.11.7372 · Cited by 156
Self-citationIto, T., Ueno, T., Clarkson, M. R., Yuan, X., Jurewicz, M. M., Yagita∥, H., Azuma, M., Sharpe, A. H., Auchincloss, H., Sayegh, M. H., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.11.6648 · Cited by 153
Self-citationExpression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells.
Eppihimer, M. J., Gunn, J., Freeman, G. J., Greenfield, E. A., Chernova, T., Erickson, J., & Leonard, J. P. (2002) · PubMed · doi:10.1038/sj/mn/7800123 · Cited by 149
The membrane attack complex of complement induces caspase activation and apoptosis
Nauta, A. J., Daha, M. R., Tijsma, O., van de Water, B., Tedesco, F., & Roos, A. (2002) · European Journal of Immunology · doi:10.1002/1521-4141(200203)32:3 · Cited by 147
Hams, E., McCarron, M. J., Amu, S., Yagita∥, H., Azuma, M., Chen, L., & Fallon, P. G. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003161 · Cited by 142 · cited 2×
“However, as discussed earlier in this review, the precise role of the PD-1 pathway in regulating T cell-dependent antibody responses is still unclear (42,43).”
BackgroundResultCD4 + CD25 + Regulatory Cells from Human Peripheral Blood Express Very High Levels of CD25 Ex Vivo
Baecher‐Allan, C., Brown, J. A., Freeman, G. J., & Hafler, D. A. (2003) · Novartis Foundation symposium · doi:10.1002/0470871628.ch6 · Cited by 136 · cited 1×
“Last, certain subsets of T cells express high levels of PD-1, including CD4+Foxp3+ regulatory T cells (Tregs) (14), T follicular helper cells (TFH) (15), memory T cells (16) and “exhausted” CD8 cells (17).”
BackgroundYang, J., Riella, L. V., Chock, S., Liu, T., Zhao, X., Yuan, X., Paterson, A. M., Watanabe, T., Vanguri, V. K., Yagita∥, H., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100056 · Cited by 136 · cited 5×
“Our studies revealed a significantly greater effect of a blocking anti-PD-L1 mAb as compared to a blocking anti-PD-1 mAb in alloimmunity (98,99).”
BackgroundMethodResultInfluentialSelf-citationAbe, M., Wang, Z., Creus, A. D., & Thomson, A. W. (2005) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2005.00954.x · Cited by 125 · cited 1×
“For example, PD-L1 expression is high in tolerogenic subsets of DCs, Tregs and mesenchymal stem cells (32,100,101), whereas the expression of PD-L2 is mostly restricted to professional APCs.”
BackgroundPD‐1/B7‐H1 Interaction Contribute to the Spontaneous Acceptance of Mouse Liver Allograft
Morita, M., Fujino, M., Jiang, G., Kitazawa, Y., Xie, L., Azuma, M., Yagita∥, H., Nagao, S., Sugioka, A., Kurosawa, Y., et al. (2009) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2009.02859.x · Cited by 122 · cited 4×
“lymphocytes and increased levels of inflammatory cytokines (92).”
BackgroundInfluentialPD-L2 is expressed on activated human T cells and regulates their function
Messal, N., Serriari, N., Pastor, S., Nunès, J. A., & Olive, D. (2011) · Molecular Immunology · doi:10.1016/j.molimm.2011.06.436 · Cited by 120 · cited 1×
“PD-L2 is also expressed on human, but not mouse, vascular endothelial cells and T cells (6,22).”
BackgroundBlank, C. U., Brown, I., Marks, R., Nishimura, H., Honjo, T., & Gajewski, T. F. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.9.4574 · Cited by 119 · cited 1×
“Two studies using the alloreactive 2C TCR transgenic model showed increased negative selection in the absence of PD-1 (53,58), while analysis of HY-specific CD4 and CD8 TCR transgenic mice revealed no role for PD-1 in negative selection (59).”
BackgroundTGF-β1 modulates Foxp3 expression and regulatory activity in distinct CD4+ T cell subsets
Pyzik, M., & Piccirillo, C. A. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.1006644 · Cited by 115
The effect of immunosuppressive drug rapamycin on regulatory CD4+CD25+Foxp3+T cells in mice
Qu, Y., Zhang, B., Zhao, L., Liu, G., Ma, H., Rao, E., Zeng, C., & Zhao, Y. X. (2007) · Transplant Immunology · doi:10.1016/j.trim.2007.01.002 · Cited by 111
Yang, J., Popoola, J., Khandwala, S., Vadivel, N., Vanguri, V. K., Yuan, X., Dada, S., Guleria, I., Tian, C., Ansari, M. J., et al. (2008) · Circulation · doi:10.1161/circulationaha.107.741025 · Cited by 98 · cited 3×
“In less allogeneic models, such as the MHC class II mismatched model (bm12 into B6), blockade of PD-L1 also precipitated rejection, whereas PD-1 and PD-L2 blockade had no effect on graft survival (96,99).”
BackgroundSelf-citationRenal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses
Starke, A., Lindenmeyer, M. T., Segerer, S., Neusser, M. A., Rüsi, B., SCHMID, D. M., Cohen, C. D., Wuthrich, R. P., Fehr, T. H., & Waeckerle‐Men, Y. (2010) · Kidney International · doi:10.1038/ki.2010.97 · Cited by 89 · cited 1×
“Furthermore, in human kidney transplantation, tubular epithelial cells were found to upregulate PD-L1 during acute allograft rejection and PDL1 on human tubular epithelial cell cultures was capable of inhibiting proliferation and cytokine production of CD4+ and CD8+ T cells (117).”
BackgroundProgrammed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance
Wang, L., Han, R., & Hancock, W. W. (2007) · European Journal of Immunology · doi:10.1002/eji.200737583 · Cited by 82 · cited 2×
“Furthermore, blockade or elimination of PD-L1 also abrogates other tolerogenic strategies, such as antiCD154 mAb combined with donor-specific transfusion (95).”
BackgroundChadha, R., Heidt, S., Jones, N. D., & Wood, K. J. (2011) · Transplantation · doi:10.1097/tp.0b013e3182126eeb · Cited by 75 · cited 1×
“Mouse models of liver transplantation (103) are very interesting to investigate, since the majority of liver grafts are”
BackgroundRiella, L. V., Watanabe, T., Sage, P. T., Yang, J., Yeung, M. Y., Azzi, J. R., Vanguri, V. K., Chandraker, A. K., Sharpe, A. H., Sayegh, M. H., et al. (2011) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2011.03451.x · Cited by 67 · cited 7×
“BALB/c PD-L1 chimera → B6 PD-L1 chimeric donor Graft PD-L1 expression on both hematopoietic and nonhematopoietic cells are essential for tolerance ↑CD8 eff mem ↑IFN-c , GrB (32)”
BackgroundMethodInfluentialSelf-citationLin, S.-J., Peacock, C. D., Bahl, K., & Welsh, R. M. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20062150 · Cited by 62 · cited 2×
“In a lymphopenic environment, a subpopulation of PD-1high T cells develop that have skewed TCR repertoires and appear to be preapoptotic (63).”
BackgroundYi, T., Li, X.-F., Yao, S., Wang, L., Chen, Y.-H., Zhao, D., Johnston, H. F., Young, J. S., Liu, H., Todorov, I., et al. (2011) · Journal of Immunology · doi:10.4049/jimmunol.1002939 · Cited by 57 · cited 2×
“Antibody blockade studies suggest that this pathway inhibits expansion of established Tregs, as well as effector T cells (89,90).”
BackgroundThangavelu, G., Parkman, J., Ewen, C., Uwiera, R. R. E., Baldwin, T. A., & Anderson, C. C. (2011) · Journal of Autoimmunity · doi:10.1016/j.jaut.2011.02.009 · Cited by 56 · cited 2×
“Two studies using the alloreactive 2C TCR transgenic model showed increased negative selection in the absence of PD-1 (53,58), while analysis of HY-specific CD4 and CD8 TCR transgenic mice revealed no role for PD-1 in negative selection (59).”
BackgroundKoehn, B. H., Ford, M. L., Ferrer, I. R., Borom, K., Gangappa, S., Kirk, A. D., & Larsen, C. P. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.8.5313 · Cited by 53 · cited 11×
“The role of PD-1 in Treg conversion was partially mediated by the activation of intracellular SHP1/2 and consequent reduction of STAT1 phosphorylation, thereby abrogating IFN-c -mediated maintenance of T-bet and favoring Foxp3 expression (81).”
BackgroundMethodInfluentialGene Transfer of Programmed Death Ligand-1.Ig Prolongs Cardiac Allograft Survival
Dudler, J., Li, J., Pagnotta, M., Pascual, M. A., von Segesser, . K., & Vassalli, G. (2006) · Transplantation · doi:10.1097/01.tp.0000250757.69384.79 · Cited by 47 · cited 2×
“F344→ Lewis (rat model) Overexpression of PD-L1 on donor heart via adenovirus ± cyclosporine Slight delay in rejection in combination with cyclosporine ↓CD4 graft infiltration (119)”
MethodWang, C., Li, Y., Proctor, T. M., Vandenbark, A. A., & Offner, H. (2009) · Journal of Neuroscience Research · doi:10.1002/jnr.22181 · Cited by 43
A Novel Alloantigen-Specific CD8+PD1+ Regulatory T Cell Induced by ICOS-B7h Blockade In Vivo
Izawa, A., Yamaura, K., Albin, M. J., Jurewicz, M. M., Tanaka, K., Clarkson, M. R., Ueno, T., Habicht, A., Freeman, G. J., Yagita∥, H., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.2.786 · Cited by 42 · cited 1×
“In addition, a subpopulation of regulatory allo-specific CD8+ T cells expressing PD-1, which is induced by ICOS: B7h blockade, was found to be important for immune regulation (91).”
BackgroundWang, R., Carper, K., Malone, F. R., Latchman, Y. E., Perkins, J. D., Fu, Y., Reyes, J. D., & Li, W. (2008) · Transplantation · doi:10.1097/tp.0b013e3181861932 · Cited by 37 · cited 7×
“PD-L1 engagement of its receptors (PD-1, and possibly B7–1) on naı̈ve T cells leads to iTreg development, at least in part, by inhibiting mTOR/Akt signaling, as shown by experiments using microbeads coated with anti-CD3, anti-CD28 and PD-L1 fusion protein as artificial APCs (77).”
InfluentialMcDermott, D. F., Drake, C. G., Sznol, M., Sosman, J. A., Smith, D. C., Powderly, J. D., Feltquate, D., Kollia, G. D., Gupta, A. K., & Wigginton, J. M. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.7_suppl.331 · Cited by 29
Memory T cells and their exhaustive differentiation in allograft tolerance and rejection
Valujskikh, A., & Li, X. C. (2011) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0b013e32834ee443 · Cited by 23 · cited 1×
“Whether “exhausted” T cells develop in the setting of alloimmunity is not known, and is a subject for future investigation (124).”
BackgroundPeng, W., Ran, B., Ma, Y., Huang, X., Chang, Q., & Wang, X. (2011) · Cellular Immunology · doi:10.1016/j.cellimm.2011.06.007 · Cited by 15 · cited 2×
“While all control rats died prior to 12 days after transplant, PD-L1-DC-treated rats had greater than 60% survival at 3 weeks posttransplant (120).”
Background
Research works printed but not linked: 1
- McDermott, 2011, A phase I study to evaluate safety and antitumor activity of biweekly BMS-936558 in patients with RCC and other advanced refractory malignancies, J Clin Oncol, 29
Cited by
Sorted by citations
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,320
Oncology meets immunology: the cancer-immunity cycle.
Chen, D. S., & Mellman, I. (2013) · Immunity · doi:10.1016/j.immuni.2013.07.012 · Cited by 6,929
Immune Checkpoint Inhibitors in Cancer Therapy
Shiravand, Y., Khodadadi, F., Kashani, S. M. A., Hosseini-Fard, S. R., Hosseini, S., Sadeghirad, H., Ladwa, R., O’Byrne, K., & Kulasinghe, A. (2022) · Current Oncology · doi:10.3390/curroncol29050247 · Cited by 1,353
“PD-1 is an inhibitor receptor, playing a key role in programmed death signaling in order to regulate T- cell mediated responses [32].”
BackgroundStructure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1
Żak, K. M., Kitel, R., Przetocka, S., Golik, P., Guzik, K., Musielak, B., Dömling, A. S. S., Dubin, G., & Holak, T. A. (2015) · Structure · doi:10.1016/j.str.2015.09.010 · Cited by 561
“Thereby, under normal conditions, the PD-1/PD-L1 pathway prevents excessive stimulation and maintains the immune tolerance to self-antigens by negatively regulating the immune response (Riella et al., 2012).”
BackgroundWu, M., Huang, Q., Xie, Y., Wu, X., Ma, H., Zhang, Y., & Xia, Y. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01242-2 · Cited by 484
“Generally, the PD-1/PD-L1 pathway prevents the overstimulation of T cells and maintains immune tolerance to self-antigens, thereby reducing damage to surrounding tissues and preventing autoimmune diseases from developing [37, 38].”
Background
Metadata
- Authors
- Riella, L. V., Paterson, A. M., Sharpe, A. H., & Chandraker, A.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Riella, L.V.
- Venue
- American Journal of Transplantation
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 12
- Issue
- 10
- Pages
- 2575-2587
- ISSN
- 1600-6135 (ISSN-L)
- PMC
- PMC3784243
- OpenAlex
- W2144601357
- Cited by
- 444
- References
- 132
- Citations by year
- 2026: 25 · 2025: 25 · 2024: 39 · 2023: 35 · 2022: 33 · 2021: 40 · 2020: 38 · 2019: 36 · 2018: 42 · 2017: 50 · 2016: 25 · 2015: 22 · 2014: 21 · 2013: 13
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Transplantation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- National Institute of Allergy and Infectious Diseases (R01AI051559, P01 AI 56299, R01 AI-51559, P01AI056299)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Keywords
- PD-1 pathway, PD-L1, PD-L2, allograft tolerance, immune regulation, regulatory T cells, peripheral tolerance, graft survival
- MeSH terms
- Graft Survival, Humans, Immune Tolerance, Lymphocyte Activation, Signal Transduction, Organ Transplantation, T-Lymphocytes, Regulatory, Programmed Cell Death 1 Receptor
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