Genomes and Genes
Gene Symbol: PD 1
Description: programmed cell death 1
Alias: Ly101, PD-1, Pdc1, programmed cell death protein 1, mPD-1, programmed cell death 1 protein, protein PD-1
Products: PD 1
- Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319-22 pubmed..These results indicate that PD-1 may be an important factor contributing to the prevention of autoimmune diseases. ..
- Currie A, Prosser A, McDonnell A, Cleaver A, Robinson B, Freeman G, et al. Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation. J Immunol. 2009;183:7898-908 pubmed publisher..Thus, PD-L1 blockade activates antitumor CD8 T cell most potently in the absence of CD4 T cells. These findings have implications for the development of PD-L1-based therapies. ..
- Lukens J, Cruise M, Lassen M, Hahn Y. Blockade of PD-1/B7-H1 interaction restores effector CD8+ T cell responses in a hepatitis C virus core murine model. J Immunol. 2008;180:4875-84 pubmed..This also suggests that manipulation of the PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent HCV infection. ..
- Blazar B, Carreno B, Panoskaltsis Mortari A, Carter L, Iwai Y, Yagita H, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol. 2003;171:1272-7 pubmed..These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN-gamma production and suggest a novel therapeutic target for inhibiting GVHD lethality. ..
- Yang J, Riella L, Chock S, Liu T, Zhao X, Yuan X, et al. The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol. 2011;187:1113-9 pubmed publisher..1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction. ..
- Cho H, Lee S, Seo S, Choi I, Choi I, Lee S. Interferon-sensitive response element (ISRE) is mainly responsible for IFN-alpha-induced upregulation of programmed death-1 (PD-1) in macrophages. Biochim Biophys Acta. 2008;1779:811-9 pubmed publisher..Our findings support the essential roles of ISRE, STAT1, and STAT2 in the regulation of constitutive and IFN-alpha-mediated PD-1 expression in macrophages. ..
- Tsushima F, Iwai H, Otsuki N, Abe M, Hirose S, Yamazaki T, et al. Preferential contribution of B7-H1 to programmed death-1-mediated regulation of hapten-specific allergic inflammatory responses. Eur J Immunol. 2003;33:2773-82 pubmed..Our results demonstrate the regulatory role of PD-1 and the differential roles of B7-H1 and B7-DC in hapten-induced immune responses. The PD-1-B7-H1 pathway may play a unique role in regulating inflammatory responses. ..
- Nishimura H, Minato N, Nakano T, Honjo T. Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol. 1998;10:1563-72 pubmed..Thus, PD-1 was suggested to be involved in the negative regulation for particular aspects of B cell proliferation and differentiation including class switching. ..
- Wang L, Pino Lagos K, de Vries V, Guleria I, Sayegh M, Noelle R. Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci U S A. 2008;105:9331-6 pubmed publisher..Collectively, this study highlights the cellular and molecular parameters that might be exploited to control the de novo generation of aTregs and peripheral tolerance. ..
- Martin Orozco N, Wang Y, Yagita H, Dong C. Cutting Edge: Programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens. J Immunol. 2006;177:8291-5 pubmed..Thus, during the presentation of tissue Ags to CD8+ T cells, PD-1/PD-L1 interaction crucially controls the effector differentiation of autoreactive T cells to maintain self-tolerance. ..
- Wang J, Okazaki I, Yoshida T, Chikuma S, Kato Y, Nakaki F, et al. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol. 2010;22:443-52 pubmed publisher..These findings unravel the hidden heart-specific autoimmune predisposition of MRL mice and provide MRL-Pdcd1(-)(/-) mice as a useful animal model of lymphocytic myocarditis. ..
- Zhong X, Bai C, Gao W, Strom T, Rothstein T. Suppression of expression and function of negative immune regulator PD-1 by certain pattern recognition and cytokine receptor signals associated with immune system danger. Int Immunol. 2004;16:1181-8 pubmed..Our data suggest a novel mechanism for enhancement of normal immune responses and disruption of normal tolerance mechanisms. ..
- Lazar Molnar E, Chen B, Sweeney K, Wang E, Liu W, Lin J, et al. Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci U S A. 2010;107:13402-7 pubmed publisher..Overall, our studies show that the PD-1 pathway is required to control excessive inflammatory responses after M. tuberculosis infection in the lungs. ..
- Rajasalu T, Brosi H, Schuster C, Spyrantis A, Boehm B, Chen L, et al. Deficiency in B7-H1 (PD-L1)/PD-1 coinhibition triggers pancreatic beta-cell destruction by insulin-specific, murine CD8 T-cells. Diabetes. 2010;59:1966-73 pubmed publisher..Hence, regulation of the susceptibility of the beta-cells for a preproinsulin-specific CD8 T-cell attack can allow or suppress EAD. ..
- Okazaki T, Otaka Y, Wang J, Hiai H, Takai T, Ravetch J, et al. Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB/c-Fcgr2b-/-Pdcd1-/- mice. J Exp Med. 2005;202:1643-8 pubmed..These observations suggest cross talk between two immunoinhibitory receptors, FcgammaRIIB and PD-1, on the regulation of autoimmune diseases. ..
- Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T. PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med. 2003;198:39-50 pubmed..These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity. ..
- Gotsman I, Grabie N, Dacosta R, Sukhova G, Sharpe A, Lichtman A. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J Clin Invest. 2007;117:2974-82 pubmed..Our findings indicate that the PD-1/PD-L pathway has an important role in downregulating proatherogenic T cell response and atherosclerosis by limiting APC-dependent T cell activation. ..
- Peng W, Liu C, Xu C, Lou Y, Chen J, Yang Y, et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-? inducible chemokines. Cancer Res. 2012;72:5209-18 pubmed publisher..Taken together, our results imply that blocking the PD-1 pathway can increase IFN-? at the tumor site, thereby increasing chemokine-dependent trafficking of immune cells into malignant disease sites. ..
- Okazaki T, Chikuma S, Iwai Y, Fagarasan S, Honjo T. A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol. 2013;14:1212-8 pubmed publisher..Such unique properties make PD-1 a powerful target for immunological therapy, with highly effective clinical applications for cancer treatment. ..
- Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141-51 pubmed..Collectively, it is suggested that PD-1 is involved in the maintenance of peripheral self-tolerance by serving as a negative regulator of immune responses. ..
- Chen Y, Wu S, Guo G, Fei L, Guo S, Yang C, et al. Programmed death (PD)-1-deficient mice are extremely sensitive to murine hepatitis virus strain-3 (MHV-3) infection. PLoS Pathog. 2011;7:e1001347 pubmed publisher..Taken together, our results suggest that PD-1 signaling plays an essential role in decreasing the immunopathological damage induced by MHV-3 and that manipulation of this signal might be a useful strategy for FH immunotherapy...
- Kido M, Watanabe N, Okazaki T, Akamatsu T, Tanaka J, Saga K, et al. Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling. Gastroenterology. 2008;135:1333-43 pubmed publisher..Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage. ..
- Fife B, Pauken K, Eagar T, Obu T, Wu J, Tang Q, et al. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol. 2009;10:1185-92 pubmed publisher..Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1-PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4...
- Fife B, Guleria I, Gubbels Bupp M, Eagar T, Tang Q, Bour Jordan H, et al. Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med. 2006;203:2737-47 pubmed
- Day C, Kaufmann D, Kiepiela P, Brown J, Moodley E, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006;443:350-4 pubmed..Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection. ..
- Bu D, Tarrio M, Maganto Garcia E, Stavrakis G, Tajima G, Lederer J, et al. Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler Thromb Vasc Biol. 2011;31:1100-7 pubmed publisher..PD-1 has an important role in downregulating proatherogenic T-cell responses, and blockade of this molecule for treatment of viral infections or cancer may increase risk of cardiovascular complications. ..
- Bhadra R, Gigley J, Weiss L, Khan I. Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade. Proc Natl Acad Sci U S A. 2011;108:9196-201 pubmed publisher..To the best of our knowledge, this report is unique in showing that exposure to a persistent pathogen despite initial control of parasitemia can lead to CD8(+) T-cell dysfunction and parasite reactivation. ..
- Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 2003;9:1477-83 pubmed..These findings suggest that antibodies to cTnI induce heart dysfunction and dilatation by chronic stimulation of Ca2+ influx in cardiomyocytes. ..
- Shin T, Kennedy G, Gorski K, Tsuchiya H, Koseki H, Azuma M, et al. Cooperative B7-1/2 (CD80/CD86) and B7-DC costimulation of CD4+ T cells independent of the PD-1 receptor. J Exp Med. 2003;198:31-8 pubmed..Finally, costimulation with B7-DC alone or in conjunction with B7-1 is PD-1 independent, indicating that B7-DC costimulates T cells via a second receptor. ..
- Kawamoto S, Tran T, Maruya M, Suzuki K, Doi Y, Tsutsui Y, et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science. 2012;336:485-9 pubmed publisher..Thus, PD-1 plays a critical role in regulation of antibody diversification required for the maintenance of intact mucosal barrier...
- Zhou Q, Munger M, Highfill S, Tolar J, Weigel B, Riddle M, et al. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood. 2010;116:2484-93 pubmed publisher..PD-1/PD-L1 blockade coupled with Treg depletion represents an important new approach that can be readily translated into the clinic to improve the therapeutic efficacy of adoptive AML-reactive CTLs in advanced AML disease...
- Blackburn S, Crawford A, Shin H, Polley A, Freeman G, Wherry E. Tissue-specific differences in PD-1 and PD-L1 expression during chronic viral infection: implications for CD8 T-cell exhaustion. J Virol. 2010;84:2078-89 pubmed publisher..These observations have implications for human chronic infections and for therapeutic interventions based on blockade of the PD-1 pathway. ..
- Charlton J, Chatzidakis I, Tsoukatou D, Boumpas D, Garinis G, Mamalaki C. Programmed death-1 shapes memory phenotype CD8 T cell subsets in a cell-intrinsic manner. J Immunol. 2013;190:6104-14 pubmed publisher..Additionally, adoptively transferred PD-1 KO T(EM) phenotype cells converted to a lesser degree to a T(CM) phenotype. Collectively, these data suggest that PD-1 shapes memory phenotype CD8 T cell subsets. ..
- Ishida M, Iwai Y, Tanaka Y, Okazaki T, Freeman G, Minato N, et al. Differential expression of PD-L1 and PD-L2, ligands for an inhibitory receptor PD-1, in the cells of lymphohematopoietic tissues. Immunol Lett. 2002;84:57-62 pubmed..Thus, present results demonstrate the distinct expression patterns of PD-L1 and PD-L2 with the cells of lymphohematopoietic tissues exclusively expressing the former. ..
- Jiang F, Yoshida T, Nakaki F, Terawaki S, Chikuma S, Kato Y, et al. Identification of QTLs that modify peripheral neuropathy in NOD.H2b-Pdcd1-/- mice. Int Immunol. 2009;21:499-509 pubmed publisher..These results indicate that NOD genetic background harbors various QTLs that modify autoimmune phenotypes either by organ-specific or by organ-non-specific manner. ..
- Wang J, Yoshida T, Nakaki F, Hiai H, Okazaki T, Honjo T. Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci U S A. 2005;102:11823-8 pubmed
- Keir M, Freeman G, Sharpe A. PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J Immunol. 2007;179:5064-70 pubmed
- Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000;191:891-8 pubmed..These results collectively indicate that PD-1 negatively regulates the beta selection and modulates the positive selection, and suggest that PD-1 deficiency may lead to the significant alteration of mature T cell repertoire. ..
- Barber D, Mayer Barber K, Feng C, Sharpe A, Sher A. CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol. 2011;186:1598-607 pubmed publisher..Thus, in the absence of the PD-1 pathway, M. tuberculosis benefits from CD4 T cell responses, and host resistance requires inhibition by PD-1 to prevent T cell-driven exacerbation of the infection. ..
- Pobezinsky L, Angelov G, Tai X, Jeurling S, Van Laethem F, Feigenbaum L, et al. Clonal deletion and the fate of autoreactive thymocytes that survive negative selection. Nat Immunol. 2012;13:569-78 pubmed publisher..Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8Î±Î±(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection. ..
- Carter L, Fouser L, Jussif J, Fitz L, Deng B, Wood C, et al. PD-1:PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol. 2002;32:634-43 pubmed..However, CD8(+) T cells may be more sensitive to modulation by the PD-1:PD-L pathway because of their intrinsic inability to produce significant levels of IL-2. ..
- Good Jacobson K, Szumilas C, Chen L, Sharpe A, Tomayko M, Shlomchik M. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat Immunol. 2010;11:535-42 pubmed publisher..PD-1 expression on T cells and PD-L2 expression on B cells controlled T(FH) cell and PC numbers. Thus, PD-1 regulates selection and survival in the GC, affecting the quantity and quality of long-lived PCs. ..
- Shimatani K, Nakashima Y, Hattori M, Hamazaki Y, Minato N. PD-1+ memory phenotype CD4+ T cells expressing C/EBPalpha underlie T cell immunodepression in senescence and leukemia. Proc Natl Acad Sci U S A. 2009;106:15807-12 pubmed publisher..The results suggest that global T cell immunodepression in senescence and leukemia is attributable to the increase in PD-1(+) MP CD4(+) T cells expressing C/EBPalpha. ..
- Raptopoulou A, Bertsias G, Makrygiannakis D, Verginis P, Kritikos I, Tzardi M, et al. The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis. Arthritis Rheum. 2010;62:1870-80 pubmed publisher..The negative costimulatory PD-1/PDL-1 pathway regulates peripheral T cell responses in both human and murine RA. PD-1/PDL-1 in rheumatoid synovium may represent an additional target for immunomodulatory therapy in RA. ..
- Goldberg M, Maris C, Hipkiss E, Flies A, Zhen L, Tuder R, et al. Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells. Blood. 2007;110:186-92 pubmed..These findings demonstrate that, in addition to modulating effector functions in the periphery, B7-H1:PD-1 interactions regulate early T-cell-fate decisions. ..
- Carter L, Leach M, Azoitei M, Cui J, Pelker J, Jussif J, et al. PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2007;182:124-34 pubmed..These results demonstrate that interactions between PD-1/PD-L1, but not PD-1/PDL-2, are crucial in attenuating T cell responses in EAE. ..
- Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19:813-24 pubmed..In this review, we would like to summarize the history of PD-1 research since its discovery and recent findings that suggest promising future for the clinical application of PD-1 agonists and antagonists to various human diseases. ..
- Kao C, Oestreich K, Paley M, Crawford A, Angelosanto J, Ali M, et al. Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection. Nat Immunol. 2011;12:663-71 pubmed publisher..Persistent antigenic stimulation caused downregulation of T-bet, which resulted in more severe exhaustion of CD8(+) T cells. Our observations suggest therapeutic opportunities involving higher T-bet expression during chronic infection...
- Zhang X, Schwartz J, Guo X, Bhatia S, Cao E, Lorenz M, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004;20:337-47 pubmed..Furthermore, our structure-based mutagenesis studies identify the ligand binding surface of PD-1, which displays significant differences compared to those present in the other members of the family. ..
- Yokosuka T, Takamatsu M, Kobayashi Imanishi W, Hashimoto Tane A, Azuma M, Saito T. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med. 2012;209:1201-17 pubmed publisher..This inhibitory mechanism also functions in PD-1(hi) T cells generated in vivo and can be overridden by a neutralizing anti-PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation. ..
- Ozkaynak E, Wang L, Goodearl A, McDonald K, Qin S, O Keefe T, et al. Programmed death-1 targeting can promote allograft survival. J Immunol. 2002;169:6546-53 pubmed
- Bhadra R, Gigley J, Khan I. PD-1-mediated attrition of polyfunctional memory CD8+ T cells in chronic toxoplasma infection. J Infect Dis. 2012;206:125-34 pubmed publisher..The conclusions of this study can have profound immunotherapeutic implications in combating recrudescent toxoplasmosis as well other chronic infections. ..
- Lazar Molnar E, Yan Q, Cao E, Ramagopal U, Nathenson S, Almo S. Crystal structure of the complex between programmed death-1 (PD-1) and its ligand PD-L2. Proc Natl Acad Sci U S A. 2008;105:10483-8 pubmed publisher..These studies define spatial and organizational constraints that control the localization and signaling of PD-1/PD-L complexes within the immunological synapse and provide a basis for manipulating the PD-1 pathways for immunotherapy. ..
- Yao S, Wang S, Zhu Y, Luo L, Zhu G, Flies S, et al. PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood. 2009;113:5811-8 pubmed publisher..Our results reveal a novel role of PD-1 in the negative regulation of DC function during innate immune response. ..
- Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger L. Activation-induced expression of human programmed death-1 gene in T-lymphocytes. Exp Cell Res. 1997;232:25-8 pubmed..These data suggest a role for hPD-1 during activation and differentiation of T-lymphocytes. ..
- Woo S, Turnis M, Goldberg M, Bankoti J, Selby M, Nirschl C, et al. Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012;72:917-27 pubmed publisher..In addition, they argue strongly that dual blockade of these molecules represents a promising combinatorial strategy for cancer. ..
- Ansari M, Salama A, Chitnis T, Smith R, Yagita H, Akiba H, et al. The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med. 2003;198:63-9 pubmed
- Reynoso E, Elpek K, Francisco L, Bronson R, Bellemare Pelletier A, Sharpe A, et al. Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade. J Immunol. 2009;182:2102-12 pubmed publisher..Collectively, these results indicate that loss of the PD-1:PD-L1 inhibitory pathway breaks CD8(+) T cell tolerance to intestinal self-Ag, thus leading to severe enteric autoimmunity. ..
- Probst H, McCoy K, Okazaki T, Honjo T, Van Den Broek M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat Immunol. 2005;6:280-6 pubmed..Thus PD-1 and CTLA-4 are crucial molecules for peripheral CD8(+) T cell tolerance induced by resting dendritic cells. ..
- Yoshida T, Jiang F, Honjo T, Okazaki T. PD-1 deficiency reveals various tissue-specific autoimmunity by H-2b and dose-dependent requirement of H-2g7 for diabetes in NOD mice. Proc Natl Acad Sci U S A. 2008;105:3533-8 pubmed publisher..In addition, 60% of the NOD-H2(b/g7)Pdcd1(-/-) mice developed diabetes, suggesting that H-2(b) does not dominantly suppress diabetes and that H-2(g7) induces diabetes in a dose-dependent fashion. ..
- Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T. Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics. 1994;23:704-6 pubmed..The human PD-1 gene was mapped to 2q37.3 by chromosomal in situ hybridization. ..