Immunologic Research

, Volume 28, Issue 1, pp 49–59 | Cite as

Cytotoxic T-lymphocyte antigen-4 and programmed death-1 function as negative regulators of lymphocyte activation

  • Laura L. Carter
  • Beatriz M. Carreno


The B7 family of ligands and receptors plays a critical role in the modulation of immune responses. The B7/cytotoxic T-lymphocyte antigen-4 (CTLA-4) and the more recently identified programmed death ligand/programmed death-1 (PD-L/PD-1) ligand/receptor pairs define pathways that function as rheostats of lymphocyte activation. Analysis of receptor and ligand expression patterns, as well as the phenotype of CTLA-4 or PD-1-deficient mice, strongly suggests that these pathways are nonredundant. Current data suggest that the B7/CTLA-4 pathway functions primarily to attenuate, limit, and/or terminate naïve T-cell activation in secondary lymphoid organs. The PD-L/PD-1 pathway, on the other hand, may primarily attenuate, limit, and/or terminate T-, B-, and myeloid cell activation/effector function at sites of inflammation in the periphery.

Key words

B7 ligands Cytotoxic T-lymphocyte antigen-4 Rogrammed death-1 T-cell receptor activation Costimulation 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Carreno BM, Collins M: The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 2002; 20:29–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Ravetch JV, Lanier LL: Immune inhibitory receptors. Science 2000;290:84–89.PubMedCrossRefGoogle Scholar
  3. 3.
    Sharpe AH, Freeman GJ: The B7-CD28 superfamily. Nat Rev Immunol 2002;2:116–126.PubMedCrossRefGoogle Scholar
  4. 4.
    Coyle AJ, Gutierrez-Ramos JC: The expanding B7 superfamily: increasing complexity in costimulatory signals regulating T cell function. Nat Immunol 2001;2: 203–209.PubMedCrossRefGoogle Scholar
  5. 5.
    Liang L, Sha WC: The right place at the right time: novel B7 family members regulate effector T cell responses. Curr Opin Immunol 2002;14:384–390.PubMedCrossRefGoogle Scholar
  6. 6.
    Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA: CTLA-4 is a second receptor for the B cell activation antigen B7. J Exp Med 1991; 174:561–569.PubMedCrossRefGoogle Scholar
  7. 7.
    Freeman GJ, Long AJ, Iwai Y, et al.: Engagement of the PD-1 immuno inhibitory receptor by a novel B7 family member leads to negative regulation of lymphocy teactivation. J Exp Med 2000;192:1027–1034.PubMedCrossRefGoogle Scholar
  8. 8.
    Latchman Y, Wood CR, Chermove T, et al.: PD-L2, a novel B7 homologue, is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001;2:261–268.PubMedCrossRefGoogle Scholar
  9. 9.
    Carter L, Fouser L, Jussif J, Fitz L, Deng B, Wood C, Collins M, Honjo T, Freeman G, Carreno B: PD-1: PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2. Eur J Immunol 2002;32:634–643.PubMedCrossRefGoogle Scholar
  10. 10.
    Schwartz J-CD, Zhang X, Nathenson SG, Almo SC: Structural mechanisms of costimulation. Nat Immunol 2002;3:427–434.PubMedCrossRefGoogle Scholar
  11. 11.
    Baroja ML, Luxenberg D, Chau T, Ling V, Strathdee CA, Carreno BM, Madrenas J: The inhibitory function of CTLA-4 does not require its tyrosine phosphorylation. J Immunol 2000;164: 49–55.PubMedGoogle Scholar
  12. 12.
    Alegre ML, Frauwirth KA, Thompson CB: T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 2001; 1:220–228.PubMedCrossRefGoogle Scholar
  13. 13.
    Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, Straus D, Samelson LE, Thompson CB, Bluestone JA: Molecular basis of T cell inactivation by CTLA-4. Science 1998;282:2263–2266.PubMedCrossRefGoogle Scholar
  14. 14.
    Baroja ML, Darlington PJ, Carreno BM, Madrenas J: Inhibition of T cell activation by CTLA-4: truths and red herrings. Mod Aspects Immunobiol 2000;1:169–173.Google Scholar
  15. 15.
    Cinek T, Sadra A, Imboden JB: Cutting edge: tyrosine-independent transmission of inhibitory signals by CTLA-4. J Immunol 2000;164:5–8.PubMedGoogle Scholar
  16. 16.
    Guntermann C, Alexander DR: CTLA-4 suppresses proximal TCR signaling in resting human CD4(+) T cells by inhibiting ZAP-70 Tyr(319) phosphorylation: a potential role for tyrosine phosphatases. J Immunol 2002;168:4420–4429.PubMedGoogle Scholar
  17. 17.
    Calvo CR, Amsen D, Kruisheek AM: Cytotoxic T lymphocyte antigen 4 (CTLA-4) interferes with extracellu-larsigral-regulated kinase (ERK) and JunNH2-terminal kinase (JNK) activation, but does not affect phosphorylation of T cell receptor zeta and ZAP70. J Exp Med 1997;186:1645–1653.PubMedCrossRefGoogle Scholar
  18. 18.
    Chuang E, Fisher TS, Morgan RW, Robbins MD, Duerr JM, Vander Heiden MG, Gardner JP, Hambor JE, Neveu MJ, Thompson CB: The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 2000;13:313–322.PubMedCrossRefGoogle Scholar
  19. 19.
    Baroja ML, Vijayakrishnan L, Bettelli E, Darlington PJ, Chau TA, Ling Y, Collins M, Carreno BM, Madrenas J, Kuchroo VK: Inhibition of CTLA-4 function by the regulatory subunit of serine/threonine phosphatase 2A. J Immunol 2002;168:5070–5078.PubMedGoogle Scholar
  20. 20.
    Egen JG, Kuhns MS, Allison JP: CTL A-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 2002;3:611–618.PubMedCrossRefGoogle Scholar
  21. 21.
    Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS: Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement. Immunity 1996;4:535–543.PubMedCrossRefGoogle Scholar
  22. 22.
    Egen JG, Allison JP: Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 2002;16:23–35.PubMedCrossRefGoogle Scholar
  23. 23.
    Darlington PJ, Baroja ML, Chau TA, Siu E, Ling V, Carreno BM, Madrenas J: Surface cytotoxic T lymphocyte-associated antigen 4 partitions within lipid rafts and relocates to the immunological synapse under conditions of inhibition of T cell activation. J Exp Med 2002;195:1337–1347.PubMedCrossRefGoogle Scholar
  24. 24.
    van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ: CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med 1997;185:393–403.PubMedCrossRefGoogle Scholar
  25. 25.
    Collins A, Brodie D, Gilbert R, Laboni A, Manso-Sancho R, Walse B, Stuart D, van der Merwe P, Davis S: The interaction properties of costimulatory molecules revisited. Immunity 2002;17:201–208.PubMedCrossRefGoogle Scholar
  26. 26.
    Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW: Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4. Science 1995;270: 985–988.PubMedCrossRefGoogle Scholar
  27. 27.
    Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 1995;3:541–547.PubMedCrossRefGoogle Scholar
  28. 28.
    Mandelbrot DA, McAdam AJ, Sharpe AH: B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). J Exp Med 1999;189: 435–440.PubMedCrossRefGoogle Scholar
  29. 29.
    Tivol EA, Boyd SD, McKeon S, Borriello F, Nickerson P, Strom TB, Sharpe AH: CTLA41g prevents lympho-proliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice. J Immunol 1997;158: 5091–5094.PubMedGoogle Scholar
  30. 30.
    Chambers CA, Kuhns MS, Egen JG, Allison JP: Ctla-4-mediated inhibition in regulation of t cell resporses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol 2001;19:565–594.PubMedCrossRefGoogle Scholar
  31. 31.
    Bachmann MF, Kohler G, Ecabert B, Mak TW, Kopf M: Cuttingedge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous. J Immunol 1999; 163:1128–1131.PubMedGoogle Scholar
  32. 32.
    Carreno BM, Bennett F, Chau TA, Ling V, Luxenberg D, Jussif J, Baroja ML, Madrenas J: C TLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression. J Immunol 2000;165:1352–1356.PubMedGoogle Scholar
  33. 33.
    Chambers CA, Sullivan TJ, Allison JP: Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells. Immunity 1997;7:885–895.PubMedCrossRefGoogle Scholar
  34. 34.
    Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP: CTLA-4-mediated inhibition of early events of T cell proliferation. J Immunol 1999;162: 5813–5820.PubMedGoogle Scholar
  35. 35.
    Ishida Y, Agata Y, Shibahara K, Honjo T: Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11:3887–3895.PubMedGoogle Scholar
  36. 36.
    Nishimura H, Honjo T: PD-1: an inhibitory immunoreceptor invo lived in peripheral tolerance. Trends Immunol 2001;22:265–268.PubMedCrossRefGoogle Scholar
  37. 37.
    Finger LR, Pu J, Wasserman R, Vibhakar R, Louie E, Hardy RR, Burrows PD, Billips LG: The human PD-1 gene: complete cDNA, genomic organization, and developmentally regulated expression in B cell progenitors. Gene 1997;197:177–187.PubMedCrossRefGoogle Scholar
  38. 38.
    Vibhakar R, Juan G, Traganos F, Darzynkiewicz Z, Finger LR: Activation-induced expression of human programmed death-1 gene in T-lymphocytes. Exp Cell Res. 1997;232:25–28.PubMedCrossRefGoogle Scholar
  39. 39.
    Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T: PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruitingsre homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 2001;98:13,866–13,871.CrossRefGoogle Scholar
  40. 40.
    Latour S, Gish G, Helgason CD, Humphries RK, Pawson T, Vellette A: Regulation of SLAM-mediated signal transduction by SAP, the X-linked lymphoproliferative gene products. Nat Immunol 2001;2:681–690.PubMedCrossRefGoogle Scholar
  41. 41.
    Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T: Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 1994;23: 704–706.PubMedCrossRefGoogle Scholar
  42. 42.
    Ling V, Wu PW, Finnerty HF, Agostino MJ, Graham JR, Chen S, Jussiff JM, Fisk GJ, Miller CP, Collins M: Assembly and annotation of human chromosome 2q33 sequence containing the CD28, CTLA4, and ICOS gene cluster: analysis by computational, comparative, and microarray approaches. Genomics 2001;78: 155–168.PubMedCrossRefGoogle Scholar
  43. 43.
    Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T: Expression of PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 1996;8:765–772.PubMedCrossRefGoogle Scholar
  44. 44.
    Dong H, Zhu G, Tamada K, Chen L: B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999;5: 1365–1369.PubMedCrossRefGoogle Scholar
  45. 45.
    Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H: B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001;193: 839–846.PubMedCrossRefGoogle Scholar
  46. 46.
    Tamura H, Dong H, Zhu G, Sica GL, Flies DB, Tamada K, Chen L: B7-H1 costimulation preferentially enhances CD28-independent T-helper cell function. Blood 2001; 97:1809–1816.PubMedCrossRefGoogle Scholar
  47. 47.
    Billiau A, Heremans H, Vermeire K, Matthys P: Immunomodulatory properties of interferon-gamma. An update. Ann NY Acad Sci 1998;856:22–32.PubMedCrossRefGoogle Scholar
  48. 48.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L: Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793–800.PubMedGoogle Scholar
  49. 49.
    Eppihimer MJ, Gunn J, Freeman GJ, Greenfield EA, Chernova T, Erickson J, Leonard JP: Expression and regulation of the PD-L1 immuno inhibitory molecule on microvascular endothelial cells. Microcirculation 2002; 9:133–145.PubMedCrossRefGoogle Scholar
  50. 50.
    Petroff MG, Chen L, Phillips TA, Hunt JS: B7 family molecules: novel immunomodulators at the maternal-fetal interface. Placenta 2002;23(Suppl. A):S95-S101.PubMedCrossRefGoogle Scholar
  51. 51.
    Perez VL, Van Parijs L, Biuckians A, Zheng XX, Strom TB, Abbas AK: Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity 1997;6:411–417.PubMedCrossRefGoogle Scholar
  52. 52.
    Greenwald RJ, Boussiotis VA, Lorsbach RB, Abbas AK, Sharpe AH: CTLA-4 regulates induction of anergy in vivo. Immunity 2001;14:145–155.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  • Laura L. Carter
    • 1
  • Beatriz M. Carreno
    • 1
  1. 1.Wyeth ResearchCambridge

Personalised recommendations