1932

Abstract

The T cell compartment of adaptive immunity provides vertebrates with the potential to survey for and respond specifically to an incredible diversity of antigens. The T cell repertoire must be carefully regulated to prevent unwanted responses to self. In the periphery, one important level of regulation is the action of costimulatory signals in concert with T cell antigen-receptor (TCR) signals to promote full T cell activation. The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen. Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response. This review primarily focuses on the cellular and molecular mechanisms of regulation by CTLA-4 and its manipulation as a strategy for tumor immunotherapy.

Loading

Article metrics loading...

/content/journals/10.1146/annurev.immunol.19.1.565
2001-04-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/immunol/19/1/annurev.immunol.19.1.565.html?itemId=/content/journals/10.1146/annurev.immunol.19.1.565&mimeType=html&fmt=ahah

Literature Cited

  1. Mueller DL, Jenkins MK, Schwartz RH. 1989. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy.. Annu. Rev. Immunol. 7:445–80 [Google Scholar]
  2. Lenschow DJ, Walunas TL, Bluestone JA. 1996. CD28/B7 system of T cell costimulation.. Annu. Rev. Immunol. 14:233–58 [Google Scholar]
  3. Martin PJ, Ledbetter JA, Morishita Y, June CH, Beatty PG, Hansen JA. 1986. A 44 kilodalton cell surface homodimer regulates interleukin 2 production by activated human T lymphocytes.. J. Immunol. 136:3282–87 [Google Scholar]
  4. Jenkins MK, Taylor PS, Norton SD, Urdahl KB. 1991. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells.. J. Immunol. 147:2461–66 [Google Scholar]
  5. Harding F, McArthur JG, Gross JA, Raulet DH, Allison JP. 1992. CD28 mediated signalling costimulates murine T cells and prevents the induction of anergy in T cell clones.. Nature 356:607–9 [Google Scholar]
  6. Sagerstrom CG, Kerr EM, Allison JP, Davis MM. 1993. Activation and differentiation requirments of primary T cells in vitro.. Proc. Natl. Acad. Sci. USA 90:8987–91 [Google Scholar]
  7. Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA. 1991. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and Interleukin 2 mRNA accumulation.. J. Exp. Med. 173:721–30 [Google Scholar]
  8. Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ. 1993. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation.. Science 262:905–7 [Google Scholar]
  9. Lenshcow DJ, Bluestone JA. 1993. T cell co-stimulation and in vivo tolerance.. Curr. Opin. Immunol. 5:747–52 [Google Scholar]
  10. Shahinian A, Pfeffer K, Lee KP, Kundig TM, Kishihara K, Wakeham A, Kawai K, Ohashi PS, Thompson CB, Mak T. 1993. Differential T cell costimulatory requirements in CD28-deficient mice.. Science 261:609–12 [Google Scholar]
  11. Kundig TM, Shahinian A, Kawai K, Mittrucker HW, Sebzda E, Bachmann MF, Mak TW, Ohashi PS. 1996. Duration of TCR stimulation determines costimulatory requirement of T cells.. Immunity 5:41–52 [Google Scholar]
  12. Borriello F, Sethna MP, Boyd SD, Schweitzer AN, Tivol EA, Jacoby D, Strom TB, Simpson EM, Freeman GJ, Sharpe AH. 1997. B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation.. Immunity 6:303–13 [Google Scholar]
  13. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MF, Golstein P. 1987. A new member of the immunoglobulin superfamily CTLA-4.. Nature 328:267–70 [Google Scholar]
  14. Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. 1994. Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors.. Immunity 1:793–801 [Google Scholar]
  15. Linsley PS, Brady W, Urnes M, Grosmaire LS, Damle NK, Ledbetter JA. 1991. CTLA-4 is a second receptor for the B cell activation antigen B7.. J. Exp. Med. 174:561–69 [Google Scholar]
  16. Greene JL, Leytze GM, Emswiler J, Peach R, Bajorath J, Cosand W, Linsley PS. 1996. Covalent Dimerization of CD28/CTLA-4 and oligomerization of CD80/86 regulate T cell costimulatory interactions.. J. Biol. Chem. 271:26762–71 [Google Scholar]
  17. Thompson CB, Allison JP. 1997. The emerging role of CTLA-4 as an immune attenuator.. Immunity 7:445–50 [Google Scholar]
  18. Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA. 1994. CTLA-4 can function as a negative regulator of T cell activation.. Immunity 1:405–13 [Google Scholar]
  19. Krummel MF, Allison JP. 1995. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.. J. Exp. Med. 182:459–65 [Google Scholar]
  20. Kearney ER, Walunas TL, Karr RW, Morton PA, Loh DY, Bluestone JA, Jenkins MK. 1995. Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4.. J. Immunol. 155:1033–36 [Google Scholar]
  21. Krummel MF, Sullivan TJ, Allison JP. 1996. Superantigen responses and costimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and in vivo.. Int. Immunity 8:519–23 [Google Scholar]
  22. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. 1995. Lymphoproliferative disorders with early lethality in mice deficient in CTLA-4.. Science 270:985–88 [Google Scholar]
  23. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.. Immunity 3:541–47 [Google Scholar]
  24. Chambers CA, Cado D, Truong T, Allison JP. 1997. Thymocyte differentiation occurs normally in the absence of CTLA-4.. Proc. Natl. Acad. Sci. USA 94:9296–9301 [Google Scholar]
  25. Nagata S, Golstein P. 1995. The Fas death factor.. Science 267:1449–56 [Google Scholar]
  26. Lucas PJ, Kim SJ, Melby SJ, Gress RE. 2000. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor beta II receptor.. J. Exp. Med. 191:1187–96 [Google Scholar]
  27. Gorelik L, Flavell RA. 2000. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease.. Immunity 12:171–81 [Google Scholar]
  28. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. 1999. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.. Immunity 11:141–51 [Google Scholar]
  29. Chambers CA, Sullivan TJ, Allison JP. 1997. Lymphoproliferation in CTLA-4- deficient mice is mediated by costimulation-dependent activation of CD4+ T cells.. Immunity 7:885–95 [Google Scholar]
  30. Lee K-M, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, Straus D, Samelson LE, Thompson CB, Bluestone JA. 1998. Molecular basis of T cell inactivation by CTLA-4.. Science 282:2263–66 [Google Scholar]
  31. Marengere LEM, Waterhouse P, Duncan GS, Mittrucker HW, Feng GS, Mak TW. 1996. Regulation of T cell receptor signaling by tryosine phosphatase SYP association with CTLA-4.. Science 272:1170–73 [Google Scholar]
  32. Tivol EA, Boyd SD, McKeon S, Borriello F, Nickerson P, Strom TB, Sharpe AH. 1997. CTLA4Ig prevents lymphoproliferation and fatal multiorgan tissue destruction in CTLA-4-deficient mice.. J. Immunol. 158:5091–94 [Google Scholar]
  33. Mandelbrot DA, McAdam AJ, Sharpe AH. 1999. 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. 189:435–40 [Google Scholar]
  34. Khattri R, Auger JA, Griffin MD, Sharpe AH, Bluestone JA. 1999. Lymphoproliferative disorder in CTLA-4 knockout mice is characterized by CD28-regulated activation of Th2 responses.. J. Immunol. 162:5784–91 [Google Scholar]
  35. Waterhouse P, Bachmann MF, Penninger JM, Ohashi PS, Mak TW. 1997. Normal thymic selection, normal viability and decreased lymphoproliferation in T cell receptor-transgenic CTLA-4-deficient mice.. Eur. J. Immunol. 27:1887–92 [Google Scholar]
  36. Chambers CA, Sullivan TJ, Truong T, Allison JP. 1998. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells.. Eur. J. Immunol. 28:3137–43 [Google Scholar]
  37. Chambers CA, Kuhns MS, Allison JP. 1999. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses.. Proc. Natl. Acad. Sci. USA 96:8603–8 [Google Scholar]
  38. Oosterwegel MA, Mandelbrot DA, Boyd SD, Lorsbach RB, Jarrett DY, Abbas AK, Sharpe AH. 1999. The role of CTLA-4 in regulating Th2 differentiation.. J. Immunol. 163:2634–39 [Google Scholar]
  39. Chambers CA, Allison JP. 1999. CTLA-4: The costimulatory molecule that doesn't: regulation of T cell responses by inhibition.. Cold Spring Harbor Symp. Quant. Biol. 1999:303–127 [Google Scholar]
  40. Bachmann MF, Waterhouse P, Speiser DE, McKall-Faienza K, Mak TW, Ohashi PS. 1998. Normal responsiveness of CTLA-4-deficient anti-viral cytoxic T cells.. J. Immunol. 160:95–100 [Google Scholar]
  41. Metz DP, Farber DL, Taylor T, Bottomly K. 1998. Differential role of CTLA-4 in regulation of resting memory versus naive CD4 T cell activation.. J. Immunol. 161:5855–61 [Google Scholar]
  42. Metzler B, Burkhart C, Wraith DC. 1999. Phenotypic analysis of CTLA-4 and CD28 expression during transient peptide-induced T cell activation in vivo.. Int. Immunol. 11:667–75 [Google Scholar]
  43. Gribben JG, Freeman GJ, Boussiotis VA, Rennert P, Jellis CL, Greenfield E, Barber M, Restivo VA, Ke X, Gray GS, Nadler LM. 1995. CTLA-4 mediates antigen-specific apoptosis of human T cells.. Proc. Natl. Acad. Sci. USA 92:811–15 [Google Scholar]
  44. Scheipers P, Reiser H. 1998. Fas-independent death of activated CD4+ T lymphocytes induced by CTLA-4 crosslinking.. Proc. Natl. Acad. Sci. USA 95:10083–88 [Google Scholar]
  45. Krummel MF, Allison JP. 1996. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells.. J. Exp. Med. 183:2533–40 [Google Scholar]
  46. Walunas TL, Bakker CY, Bluestone JA. 1996. CTLA-4 ligation blocks CD28-dependent T cell activation.. J. Exp. Med. 183:2541–50 [Google Scholar]
  47. Calvo CR, Amsen D, Kruisbeek AM. 1997. Cytotoxic lymphocyte antigen 4 (CTLA-4) interferes with extracellular signal-regulated kinase (ERK) and Jun NH2-terminal kinase (JNK) activation, but does not affect phophorylation of T cell receptor ζ and ZAP70.. J. Exp. Med. 186:1645–53 [Google Scholar]
  48. Chen W, Jin W, Wahl SM. 1998. Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells.. J. Exp. Med. 188:1849–57 [Google Scholar]
  49. Blair PJ, Riley JL, Levine BL, Lee KP, Craighead N, Francomano T, Perfetto SJ, Gray GS, Carreno BM, June CH. 1998. CTLA-4 ligation delivers a unique signal to resting human CD4 T cells that inhibits interleukin-2 secretion but allows Bcl-Xl induction.. J. Immunol. 160:12–15 [Google Scholar]
  50. Van Parijs L, Refaeli Y, Lord JD, Nelson BH, Abbas AK, Baltimore D. 1999. Uncoupling IL-2 signals that regulate T cell proliferation, survival, and Fas-mediated activation-induced cell death.. Immunity 11:281–88 [Google Scholar]
  51. Fraser JD, Weiss A. 1992. Regulation of T-cell lymphokine gene transcription by the accessory molecule CD28.. Mol. Cell. Biol. 12:4357–63 [Google Scholar]
  52. Lindsten T, June CH, Ledbetter JA, Stella G, Thompson CB. 1989. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway.. Science 244:339–43 [Google Scholar]
  53. Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. 1999. CTLA-4-mediated inhibition of early events of T cell proliferation.. J. Immunol. 162:5813–20 [Google Scholar]
  54. Lindsten T, Lee KP, Harris ES, Petryniak B, Craighead N, Reynolds PJ, Lombard DB, Freeman GJ, Nadler LM, Gray GS, Thompson CB, June CH. 1993. Characterization of CTLA-4 structure and expression on human T cells.. J. Immunol. 151:3489–99 [Google Scholar]
  55. Leung HT, Bradshaw J, Cleaveland JS, Linsley PS. 1995. Cytotoxic T lymphocyte-associated molecule-4, a high avidity receptor for CD80 and CD86, contains an intracellular localization motif in its cytoplasmic tail.. J. Biol. Chem. 270:25107–14 [Google Scholar]
  56. Oki S, Kohsaka T, Azuma M. 1999. Augmentation of CTLA-4 expression by wortmannin: involvement of lysosomal sorting properties of CTLA-4.. Int. Immunol. 11:1563–71 [Google Scholar]
  57. Schneider H, Martin M, Agarraberes FA, Yin L, Rapaport I, Kirchhausen T, Rudd CE. 1999. Cytolytic T lymphocyte-associated antigen-4 and the TCRζ/CD3 comples, but not CD28, interact with clathrin adaptor complexes AP-1 and AP-2.. J. Immunol. 163:1868–79 [Google Scholar]
  58. Shiratori T, Miyatake S, Ohno H, Nakaseko C, Isono K, Bonifacino JS, Saito T. 1997. Tyrosine phosphorylation controls internalization of CTLA-4 by regulating its interaction with clathrin-associated adaptor complex AP-2.. Immunity 6:583–89 [Google Scholar]
  59. Chuang E, Alegre ML, Duckett CS, Noel PJ, Vander Heiden MG, Thompson CB. 1997. Interaction of CTLA-4 with the clathrin-associated protein AP50 results in ligand-independent endocytosis that limits cell surface expression.. J. Immunol. 159:144–51 [Google Scholar]
  60. Bradshaw JD, Lu P, Leytze G, Rodgers J, Schieven GL, Bennett KL, Linsley PS, Kurtz SE. 1997. Interaction of the cytoplasmic tail of CTLA-4 (CD152) with a clathrin- associated protein is negatively regulated by tyrosine phosphorylation.. Biochemistry 36:15975–82 [Google Scholar]
  61. Zhang Y, Allison JP. 1997. Interaction of CTLA-4 with AP50, a clathrin-coated pit adaptor protein.. Proc. Natl. Acad. Sci. USA 94:9273–78 [Google Scholar]
  62. Barrat FJ, Le Deist F, Benkerrou M, Bousso P, Feldmann J, Fischer A, De Saint Basile G. 1999. Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation.. Proc. Natl. Acad. Sci. USA 96:8645–50 [Google Scholar]
  63. Cefai D, Schneider H, Matangkasombut O, Kang H, Brody J, Rudd CE. 1998. CD28 receptor endocytosis is targeted by mutations that disrupt phosphatidylinositol 3-kinase binding and costimulation.. J. Immunol. 160:2223–30 [Google Scholar]
  64. Gross JA, St.John T, Allison JP. 1990. The murine homolog of the T lymphocyte antigen CD28: molecular cloning and cell surface expression.. J. Immunol. 144:3201–10 [Google Scholar]
  65. Linsley PS, Bradshaw J, Greene J, Peach R, Bennett KL, Mittler RS. 1996. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement.. Immunity 4:535–43 [Google Scholar]
  66. Kupfer A, Swain SL, Singer SJ. 1987. The specific direct interaction of helper T cells and antigen-presenting B cells.. II. Reorientation of the microtubule organizing center and reorganization of the membrane-associated cytoskeleton inside the bound helper T cells J. Exp. Med. 165:1565–80 [Google Scholar]
  67. Shapiro VS, Truitt KE, Imboden JB, Weiss A. 1997. CD28 mediates transcriptional upregulation of the interleukin-2 (IL-2) promoter through a composite element containing the CD28RE and NF-IL-2B AP-1 sites.. Mol. Cell. Biol. 17:4051–58 [Google Scholar]
  68. Su B, Jacinto E, Hibi M, Kallunki T, Karin M, Ben-Neriah Y. 1994. JNK is involved in signal integration during costimulation of T lymphocytes.. Cell 77:727–36 [Google Scholar]
  69. Monks CR, Kupfer H, Tamir I, Barlow A, Kupfer A. 1997. Selective modulation of protein kinase C-theta during T-cell activation.. Nature 385:83–86 [Google Scholar]
  70. Wulfing C, Davis MM. 1998. A receptor/cytoskeletal movement triggered by costimulation during T cell activation.. Science 282:2266–69 [Google Scholar]
  71. Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML. 1999. The immunological synapse: a molecular machine controlling T cell activation.. Science 285:221–27 [Google Scholar]
  72. Viola A, Schroeder S, Sakakibara Y, Lanzavecchia A. 1999. T lymphocyte costimulation mediated by reorganization of membrane microdomains.. Science 283:680–82 [Google Scholar]
  73. Langlet C, Bernard AM, Drevot P, He HT. 2000. Membrane rafts and signaling by the multichain immune recognition receptors.. Curr. Opin. Immunol. 12:250–55 [Google Scholar]
  74. Hutchcroft JE, Bierer BE. 1996. Signaling through CD28/CTLA-4 family receptors: puzzling participation of phosphatidylinositol-3 kinase.. J. Immunol. 156:4071–74 [Google Scholar]
  75. Vivier E, Daëron M. 1997. Immunoreceptor tyrosine-based inhibition motifs.. Immunol. Today 18:286–91 [Google Scholar]
  76. Chambers CA, Allison JP. 1996. The role of tyrosine phosphorylation and PTP-1C in CTLA-4 signal transduction.. Eur.J. Immunol. 26:3224–9 [Google Scholar]
  77. Chuang E, Lee KM, Robbins MD, Duerr JM, Alegre ML, Hambor JE, Neveu MJ, Bluestone JA, Thompson CB. 1999. Regulation of cytotoxic T lymphocyte-associated molecule-4 by Src kinases.. J. Immunol. 162:1270–77 [Google Scholar]
  78. Schneider H, Rudd CE. 2000. Tyrosine phosphatase SHP-2 binding to CTLA-4: absence of direct YVKM/YFIP motif recognition.. Biochem. Biophys. Res. Commun. 269:279–83 [Google Scholar]
  79. Chikuma S, Murakami M, Tanaka K, Uede T. 2000. Janus kinase 2 is associated with a box 1-like motif and phosphorylates a critical tyrosine residue in the cytoplasmic region of cytotoxic T lymphocyte associated molecule-4.. J. Cell. Biochem. 78:241–50 [Google Scholar]
  80. Chuang E, Fisher TS, Morgan RW, Robbins MD, Duerr JM, Vander Heiden MG, Gardner JP, Hambor JE, Neveu MJ, Thompson CB. 2000. The CD28 and CTLA-4 receptors associated with the serine/threonine phosphatase PP2A.. Immunity 13:313–22 [Google Scholar]
  81. Calvo CR, Amsen D, Kruisbeek AM. 1997. Cytotoxic T lymphocyte antigen 4 (CTLA-4) interferes with extracellular signal-regulated kinase (ERK) and Jun NH2-terminal kinase (JNK) activation, but does not affect phosphorylation of T cell receptor zeta and ZAP70.. J. Exp. Med. 186:1645–53 [Google Scholar]
  82. Nakaseko C, Miyatake S, Iida T, Hara S, Abe R, Ohno H, Saito Y, Saito T. 1999. Cytotoxic T lymphocyte antigen 4 (CTLA-4) engagement delivers an inhibitory signal through the membrane-proximal region in the absence of the tyrosine motif in the cytoplasmic tail.. J. Exp. Med. 190:765–74 [Google Scholar]
  83. Carreno BM, Bennett F, Chau TA, Ling V, Luxenberg D, Jussif J, Baroja ML, Madrenas J. 2000. CTLA-4 (CD152) can inhibit T cell activation by two different mechanisms depending on its level of cell surface expression.. J. Immunol. 165:1352–56 [Google Scholar]
  84. Baroja ML, Luxenberg D, Chau T, Ling V, Strathdee CA, Carreno BM, Madrenas J. 2000. The inhibitory function of CTLA-4 does not require its tyrosine phosphorylation.. J. Immunol. 164:49–55 [Google Scholar]
  85. Masteller EL, Chuang E, A.C M, Reiner SL, Thompson CB. 2000. Structural analysis of CTLA-4 function in vivo.. J. Immunol. 164:5319–27 [Google Scholar]
  86. Ikemizu S, Gilbert RJC, Fennelly JA, Collins AV, Harlos K, Jones EY, Stuart DI, Davis SJ. 2000. Structure and dimerization of a soluble form of B7-1.. Immunity 12:51–60 [Google Scholar]
  87. Ostrov DA, Shi W, Schwartz J-CD, Almo SC, Nathenson SG. 2000. Structure of murine CTLA-4: a novel dimer modulating T cell responsiveness.. Science 290:816–19 [Google Scholar]
  88. Jenkins MK. 1994. The ups and downs of costimulation.. Immunity 1:443–45 [Google Scholar]
  89. Chambers CA, Krummel MF, Boitel B, Hurwitz AA, Sullivan TJ, Fournier S, Cassell D, Brunner M, Allison JP. 1996. The role of CTLA-4 in the regulation and initiation of T cell responses.. Immunol. Rev. 153:27–46 [Google Scholar]
  90. Luhder F, Hoglund P, Allison JP, Benoist C, Mathis D. 1997. CTLA-4 regulates the unfolding of autoimmune diabetes.. J. Exp. Med. 187:427–32 [Google Scholar]
  91. Luhder F, Chambers CA, Allison JP, Benoist C, Mathis D. 2000. Pinpointing when CTLA-4 must be engaged to dampen diabetogenic T cells.. Proc. Natl. Acad. Sci. USA 97:12204–9 [Google Scholar]
  92. van Oers NSC, Killeen N, Weiss A. 1994. ZAP-70 is constitutively associated with tyrosine-phosphoryated TCR z in murine thymocytes and lymph node cells.. Immunity 1:675–85 [Google Scholar]
  93. Goldrath AW, Bevan MJ. 1999. Selecting and maintaining a diverse T-cell repertoire.. Nature 402:255–62 [Google Scholar]
  94. Seddon B, Legname G, Tomlinson P, Zamoyska R. 2000. Long-term survival but impaired homeostatic proliferation of naive T cells in the absence of p56(lck).. Science 290:127–31 [Google Scholar]
  95. Dorfman JR, Stefanova I, Yasutomo K, Germain RN. 2000. CD4+ T cell survival is not directly linked to self-MHC-induced TCR signaling.. Nat. Immunol. 1:329–35 [Google Scholar]
  96. Gozalo Sanmillan, McNally J, Lin M-Y, Chambers CA, Berg LJ. Two distinct mechanisms lead to impaired T cell homeostasis in JAK3- and CTLA-4-deficient mice.. J. Immunol. In press [Google Scholar]
  97. Martin WD, Hicks GG, Mendiratta SK, Leva HI, Ruley HE, Van Kaer L. 1996. H2-M mutant mice are defective in the peptide loading of class II molecules, antigen presentation, and T cell repertoire selection.. Cell 84:543–50 [Google Scholar]
  98. Miyazaki T, Wolf P, Tourne S, Waltzinger C, Dierich A, Barois N, Ploegh H, Benoist C, Mathis D. 1996. Mice lacking H2-M complexes, enigmatic elements of the MHC class II peptide-loading pathway.. Cell 84:531–41 [Google Scholar]
  99. Chambers CA, Kang J, Wu Y, Held W, Raulet D, Allison JP. 2000. The lymphoproliferative defect in CTLA-4-deficient mice is ameliorated by the inhibitory NK cell receptor Ly49A.. Submitted
  100. Karandikar NJ, Vanderlugt CL, Walunas TL, Miller SD, Bluestone JA. 1996. CTLA-4: A negative regulator of autoimmune disease.. J. Exp. Med. 184:783–88 [Google Scholar]
  101. Perrin PJ, Maldonado JH, Davis TA, June CH, Racke MK. 1996. CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis.. J. Immunol. 157:1333–36 [Google Scholar]
  102. Hurwitz AA, Sullivan TJ, Krummel MF, Sobel RA, Allison JP. 1997. Specific blockade of CTLA-4/B7 interactions results in exacerbated clinical and histologic disease in an actively-induced model of experimental allergic encephalomyelitis.. J. Neuroimmunol. 73:57–62 [Google Scholar]
  103. Karandikar NJ, Eagar TN, Vanderlugt CL, Bluestone JA, Miller SD. 2000. CTLA-4 downregulates epitope spreading and mediates remission in relapsing experimental autoimmune encephalomyelitis.. J. Neuroimmunol. 109:173–80 [Google Scholar]
  104. Hurwitz AA, Yu TF, Leach DR, Allison JP. 1998. CTLA-4 blockade synergizes with tumor-derived GM-CSF for treatment of an experimental mammary carcinoma.. Proc. Natl. Acad. Sci. USA 95:10067–71 [Google Scholar]
  105. van Elsas A, Hurwitz AA, Allison JP. 1999. Combination immunotherapy of B16 melanoma using anti-CTLA-4 and GM-CSF producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation.. J. Exp. Med. 190:355–66 [Google Scholar]
  106. Hurwitz AA, Foster BA, Kwon ED, Trong T, Choi EM, Greenberg NM, Burg MB, Allison JP. 2000. Combination immunotherapy of primary prostate cancer in a transgenic model using CTLA-4 blockade.. Cancer Res. 60:2444–48 [Google Scholar]
  107. McCoy KD, Hermans IF, Fraser JH, Le Gros G, Ronchese F. 1999. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) can regulate dendritic cell-induced activation and cytotoxicity of CD8+ T cells independently of CD4+ T cell help.. J. Exp. Med. 189:1157–62 [Google Scholar]
  108. Kuhns MS, Epshteyn V, Sobel RA, Allison JP. 2000. CTLA-4 regulates the size, function, and reactivity of a primed pool of T cells.. Proc. Natl. Acad. Sci. USA 97:12711–16 [Google Scholar]
  109. Alegre ML, Shiels H, Thompson CB, Gajewski TF. 1998. Expression and function of CTLA-4 in Th1 and Th2 cells.. J. Immunol. 161:3347–56 [Google Scholar]
  110. Kato T, Nariuchi H. 2000. Polarization of naive CD4+ T cells toward the Th1 subset by CTLA-4 costimulation.. J. Immunol. 164:3554–62 [Google Scholar]
  111. Walunas TL, Bluestone JA. 1998. CTLA-4 regulates tolerance induction and T cell differentiation in vivo.. J. Immunol. 160:3855–60 [Google Scholar]
  112. McCoy K, Camberis M, Gros GL. 1997. Protective immunity to nematode infection is induced by CTLA-4 blockade.. J. Exp. Med. 186:183–87 [Google Scholar]
  113. Saha B, Chattopadhyay S, Germond R, Harlan DM, Perrin PJ. 1998. CTLA4 (CD152) modulates the Th subset response and alters the course of experimental Leishmania major infection.. Eur. J. Immunol. 28:4213–20 [Google Scholar]
  114. Piganelli JD, Poulin M, Martin T, Allison JP, Haskins K. 2000. Cytotoxic T lymphocyte antigen 4 (CD152) regulates self-reactive T cells in BALB/c but not in the autoimmune NOD mouse.. J. Autoimmun. 14:123–31 [Google Scholar]
  115. Constant SL, Bottomly K. 1997. Induction of Th1 and Th2 CD4+ T cell responses: the alternative approaches.. Annu. Rev. Immunol. 15:297–322 [Google Scholar]
  116. Freeman GJ, Lombard DB, Gimmi CD, Brod SA, Lee K, Laning JC, Hafler DA, Dorf ME, Gray GS, Reiser H, June CH, Thompson CB, Nadler LM. 1992. CTLA-4 and CD28 mRNA are coexpressed in most T cells after activation.. J. Immunol. 149:3705–3801 [Google Scholar]
  117. Perez VL, Van Parijs L, Biuckians A, Zheng XX, Strom TB, Abbas AK. 1997. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement.. Immunity 6:411–17 [Google Scholar]
  118. Van Parijs L, Perez VL, Biuckians A, Maki RG, London CA, Abbas AK. 1997. Role of interleukin 12 and costimulation in T cell anergy in vivo.. J. Exp Med 186:1119–28 [Google Scholar]
  119. Tsitoura DC, DeKruyff RH, Lamb JR, Umetsu DT. 1999. Intranasal exposure to protein antigen induces immunological tolerance mediated by functionally disabled CD4+ T cells.. J. Immunol. 163:2592–2600 [Google Scholar]
  120. Frauwirth KA, Alegre M-L, Thompson CB. 2000. Induction of T cell anergy in the absence of CTLA-4/B7 interaction.. J. Immunol. 164:2987–93 [Google Scholar]
  121. Gomes NA, Gattass CR, Barreto-de-Souza V, Wilson ME, DosReis GA. 2000. TGF-β mediates CTLA-4 suppression of cellular immunity in murine kalaazar.. J. Immunol. 164:2001–8 [Google Scholar]
  122. Bachmann MF, Köhler G, Ecabert B, Mak TW, Kopf M. 1999. Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous.. J. Immunol. 163:1128–31 [Google Scholar]
  123. Sullivan TJ. 2000. Characterizing the Function of CTLA-4 In Vitro and In Vivo. Berkeley, CA: Univ. Calif. Press 148 pp. [Google Scholar]
  124. Shevach EM. 2000. Regulatory T cells in autoimmmunity.. Annu. Rev. Immunol. 18:423–49 [Google Scholar]
  125. Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA. 2000. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes.. Immunity 12:431–40 [Google Scholar]
  126. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. 2000. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.. J. Exp. Med. 192:303–10 [Google Scholar]
  127. Read S, Malmstrom V, Powrie F. 2000. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.. J. Exp. Med. 192:295–302 [Google Scholar]
  128. Thornton AM, Shevach EM. 1998. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.. J. Exp. Med. 188:287–96 [Google Scholar]
  129. Sutmuller RPM, van Duivenvoorde L, van Elsas A, Allison JP, Toes REM, Melief CJM, Offringa R. 2000. CTLA-4 and CD25 constitute independent mechanisms of inhibition of auto-reactive cytotoxic T lymphocytes.. Submitted
  130. Allison JP, Hurwitz AA, Leach DR. 1995. Manipulation of costimulatory signals to enhance antitumor T-cell responses.. Curr. Opin. Immunol. 7:682–86 [Google Scholar]
  131. Leach D, Krummel M, Allison JP. 1996. Enhancement of antitumor immunity by CTLA-4 blockade.. Science 271:1734–36 [Google Scholar]
  132. Yang Y, Zou J, Mu J, Wijesuriya R, Ono S, Walunas T, Bluestone J, Fujiwara H, Hamaoka T. 1997. Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages.. Cancer Res. 57:4036–41 [Google Scholar]
  133. Hurwitz AA, van Elsas A, Leach D, Ziskin J, Villasenor J, Truong T, Allison JP. 1999. Manipulation of T cell activation to generate antitumor CTLs. In Cytotoxic Cells: Basic Mechanisms and Medical Applications, ed. MV Sitovsky, PA Henkart 385–93 Philadelphia, PA: Lippincott Williams & Wilkins
  134. Shrikant P, Khoruts A, Mescher MF. 1999. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+T cell and IL-2 dependent mechanism.. Immunity 11:483–93 [Google Scholar]
  135. Sotomayor EM, Borrello IM, Tubb E, Allison JP, Levitsky HI. 1999. In vivo blockade of CTLA-4 enhances the priming of responsive T-cells but fails to prevent the induction of tumor antigen-specific tolerance.. Proc. Natl. Acad. Sci. USA 96:11476–81 [Google Scholar]
  136. Dranoff G, Jaffee E, Lazenby A, Golumbek P, Levitsky H, Brose K, Jackson V, Hamada H, Pardoll D, Mulligan RC. 1993. Vaccination with irradiated tumor cells engineered to secrete GM-CSF stimulates potent, specific, and long lasting anti-tumor immunity.. Proc. Natl. Acad. Sci. USA 90:3539–43 [Google Scholar]
  137. Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H. 1994. Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens.. Science 264:961–65 [Google Scholar]
  138. Mokyr MB, Kalinichenko T, Gorelik L, Bluestone JA. 1998. Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice.. Cancer Res. 58:5301–4 [Google Scholar]
  139. Kwon ED, Foster BA, Hurwitz AA, Madias C, Allison JP, Greenberg NM, Burg MB. 1999. Elimination of residual metastatic prostate cancer following surgery and adjuncitve CTLA-4 blockade immunotherapy.. Proc. Natl. Acad. Sci. USA 96:15074–79 [Google Scholar]
  140. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H. 1998. The central role of CD4+ T cells in the antitumor immune response.. J. Exp. Med. 188:2357–68 [Google Scholar]
/content/journals/10.1146/annurev.immunol.19.1.565
Loading
/content/journals/10.1146/annurev.immunol.19.1.565
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error