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PMID: 15728465 Published · ppublish English Journal Article

CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 174 ·No. 5 ·2005-03-01 ·Pages 2591-601

Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP

Abstract

CD4(+) T cells control the effector function, memory, and maintenance of CD8(+) T cells. Paradoxically, we found that absence of CD4(+) T cells enhanced adoptive immunotherapy of cancer when using CD8(+) T cells directed against a persisting tumor/self-Ag. However, adoptive transfer of CD4(+)CD25(-) Th cells (Th cells) with tumor/self-reactive CD8(+) T cells and vaccination into CD4(+) T cell-deficient hosts induced autoimmunity and regression of established melanoma. Transfer of CD4(+) T cells that contained a mixture of Th and CD4(+)CD25(+) T regulatory cells (T(reg) cells) or T(reg) cells alone prevented effective adoptive immunotherapy. Maintenance of CD8(+) T cell numbers and function was dependent on Th cells that were capable of IL-2 production because therapy failed when Th cells were derived from IL-2(-/-) mice. These findings reveal that Th cells can help break tolerance to a persisting self-Ag and treat established tumors through an IL-2-dependent mechanism, but requires simultaneous absence of naturally occurring T(reg) cells to be effective.

MeSH Terms
Animals CD4-Positive T-Lymphocytes/immunology,transplantation CD8-Positive T-Lymphocytes/immunology Cell Proliferation Homeostasis/immunology Immunity, Innate Immunotherapy, Adoptive/adverse effects,methods Interleukin-2/physiology,therapeutic use Lymphocyte Activation/immunology Melanoma, Experimental/immunology,pathology,therapy Membrane Glycoproteins/biosynthesis,immunology Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Neoplasm Proteins/biosynthesis,immunology Receptors, Interleukin-2/biosynthesis Self Tolerance/immunology T-Lymphocytes, Regulatory/immunology,transplantation Transplantation Tolerance/immunology Tumor Escape/immunology gp100 Melanoma Antigen
Chemicals
Interleukin-2 Membrane Glycoproteins Neoplasm Proteins Pmel protein, mouse Receptors, Interleukin-2 gp100 Melanoma Antigen
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Antony Paul A
Division of Surgery, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. [email protected]
Piccirillo Ciriaco A
Akpinarli Akgül
Finkelstein Steven E
Speiss Paul J
Surman Deborah R
Palmer Douglas C
Chan Chi-Chao
Klebanoff Christopher A
Overwijk Willem W
Rosenberg Steven A
Restifo Nicholas P
References (61)
61 references, click to expand
  1. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism.
    Immunity. 1999 Oct;11(4):483-93 PMID: 10549630
  2. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity.
    J Immunol. 1999 Nov 15;163(10):5211-8 PMID: 10553041
  3. Vaccination with a recombinant vaccinia virus encoding a "self" antigen induces autoimmune vitiligo and tumor cell destruction in mice: requirement for CD4(+) T lymphocytes.
    Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2982-7 PMID: 10077623
  4. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.
    J Exp Med. 1998 Jul 20;188(2):287-96 PMID: 9670041
  5. CD25- T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion.
    J Immunol. 2004 Dec 15;173(12):7259-68 PMID: 15585848
  6. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance.
    J Immunol. 1999 May 1;162(9):5317-26 PMID: 10228007
  7. CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells.
    Eur J Immunol. 2000 Jun;30(6):1538-43 PMID: 10898488
  8. Eradication of established tumors by CD8+ T cell adoptive immunotherapy.
    Immunity. 2000 Aug;13(2):265-76 PMID: 10981969
  9. Tumor-specific CD4+ T cells have a major "post-licensing" role in CTL mediated anti-tumor immunity.
    J Immunol. 2000 Dec 1;165(11):6047-55 PMID: 11086036
  10. The role of MHC class II-restricted tumor antigens and CD4+ T cells in antitumor immunity.
    Trends Immunol. 2001 May;22(5):269-76 PMID: 11323286
  11. Progress in human tumour immunology and immunotherapy.
    Nature. 2001 May 17;411(6835):380-4 PMID: 11357146
  12. Autoimmunity and the immunotherapy of cancer: targeting the "self" to destroy the "other".
    Crit Rev Immunol. 2000;20(6):433-50 PMID: 11396680
  13. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells.
    J Immunol. 2001 Aug 1;167(3):1137-40 PMID: 11466326
  14. The risk of autoimmunity associated with tumor immunotherapy.
    Nat Immunol. 2001 Sep;2(9):789-92 PMID: 11526387
  15. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses.
    J Exp Med. 2001 Sep 17;194(6):823-32 PMID: 11560997
  16. Interleukin-2 fusion toxin: targeted therapy for cutaneous T cell lymphoma.
    Ann N Y Acad Sci. 2001 Sep;941:166-76 PMID: 11594570
  17. Cutting edge: precursor frequency affects the helper dependence of cytotoxic T cells.
    J Immunol. 2002 Feb 1;168(3):977-80 PMID: 11801627
  18. Do CD4+ CD25+ immunoregulatory T cells hinder tumor immunotherapy?
    J Immunother. 2002 May-Jun;25(3):202-6 PMID: 12000861
  19. Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease.
    J Immunol. 2002 Jun 15;168(12):5979-83 PMID: 12055202
  20. Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells.
    J Exp Med. 2002 Jun 17;195(12):1523-32 PMID: 12070280
  21. CD4+ CD25+ suppressor T cells: more questions than answers.
    Nat Rev Immunol. 2002 Jun;2(6):389-400 PMID: 12093005
  22. T cell homeostatic proliferation elicits effective antitumor autoimmunity.
    J Clin Invest. 2002 Jul;110(2):185-92 PMID: 12122110
  23. Origin of regulatory T cells with known specificity for antigen.
    Nat Immunol. 2002 Aug;3(8):756-63 PMID: 12089509
  24. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2.
    Immunity. 2002 Aug;17(2):167-78 PMID: 12196288
  25. CD8 lethargy in the absence of CD4 help.
    Eur J Immunol. 2002 Aug;32(8):2199-207 PMID: 12209632
  26. Interleukin 2 signaling is required for CD4(+) regulatory T cell function.
    J Exp Med. 2002 Sep 16;196(6):851-7 PMID: 12235217
  27. Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers.
    J Immunol. 2002 Nov 1;169(9):4850-60 PMID: 12391195
  28. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes.
    Science. 2002 Oct 25;298(5594):850-4 PMID: 12242449
  29. Adoptive therapy with CD8(+) T cells: it may get by with a little help from its friends.
    J Clin Invest. 2002 Nov;110(10):1415-7 PMID: 12438439
  30. Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens.
    Eur J Immunol. 2002 Nov;32(11):3267-75 PMID: 12555672
  31. CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes.
    Nature. 2003 Feb 20;421(6925):852-6 PMID: 12594515
  32. Natural versus adaptive regulatory T cells.
    Nat Rev Immunol. 2003 Mar;3(3):253-7 PMID: 12658273
  33. Defective CD8 T cell memory following acute infection without CD4 T cell help.
    Science. 2003 Apr 11;300(5617):339-42 PMID: 12690202
  34. Depletion of CD25+ regulatory cells results in suppression of melanoma growth and induction of autoreactivity in mice.
    Cancer Immun. 2002 Feb 22;2:1 PMID: 12747746
  35. Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo.
    J Exp Med. 2003 Jul 21;198(2):249-58 PMID: 12874258
  36. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells.
    J Exp Med. 2003 Aug 18;198(4):569-80 PMID: 12925674
  37. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state.
    J Exp Med. 2003 Sep 1;198(5):737-46 PMID: 12939344
  38. Essential role for STAT5 signaling in CD25+CD4+ regulatory T cell homeostasis and the maintenance of self-tolerance.
    J Immunol. 2003 Oct 1;171(7):3435-41 PMID: 14500638
  39. Cutting edge: self-peptides drive the peripheral expansion of CD4+CD25+ regulatory T cells.
    J Immunol. 2003 Dec 1;171(11):5678-82 PMID: 14634074
  40. IL-21 induces tumor rejection by specific CTL and IFN-gamma-dependent CXC chemokines in syngeneic mice.
    J Immunol. 2004 Feb 1;172(3):1540-7 PMID: 14734732
  41. Priming of naive T cells inside tumors leads to eradication of established tumors.
    Nat Immunol. 2004 Feb;5(2):141-9 PMID: 14704792
  42. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells.
    Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1969-74 PMID: 14762166
  43. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses.
    Annu Rev Immunol. 2004;22:531-62 PMID: 15032588
  44. IL-2, regulatory T cells, and tolerance.
    J Immunol. 2004 Apr 1;172(7):3983-8 PMID: 15034008
  45. Shedding light on immunotherapy for cancer.
    N Engl J Med. 2004 Apr 1;350(14):1461-3 PMID: 15070799
  46. Homeostatic expansion of T cells during immune insufficiency generates autoimmunity.
    Cell. 2004 Apr 16;117(2):265-77 PMID: 15084263
  47. Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function.
    J Immunol. 2004 Jun 1;172(11):6519-23 PMID: 15153463
  48. Helping the CD8(+) T-cell response.
    Nat Rev Immunol. 2004 Aug;4(8):595-602 PMID: 15286726
  49. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function.
    Eur J Immunol. 2004 Sep;34(9):2480-8 PMID: 15307180
  50. CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection.
    Nat Immunol. 2004 Sep;5(9):927-33 PMID: 15300249
  51. Tolerance, not immunity, crucially depends on IL-2.
    Nat Rev Immunol. 2004 Sep;4(9):665-74 PMID: 15343366
  52. T-cell-mediated suppression of anti-tumor immunity. An explanation for progressive growth of an immunogenic tumor.
    J Exp Med. 1980 Jan 1;151(1):69-80 PMID: 6444236
  53. Interleukin 2 (IL-2) augments transcription of the IL-2 receptor gene.
    Proc Natl Acad Sci U S A. 1985 Jun;82(12):4230-4 PMID: 2987968
  54. Immune responses in interleukin-2-deficient mice.
    Science. 1993 Nov 12;262(5136):1059-61 PMID: 8235625
  55. CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection.
    J Virol. 1994 Dec;68(12):8056-63 PMID: 7966595
  56. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation.
    J Exp Med. 1996 Aug 1;184(2):387-96 PMID: 8760792
  57. Interleukin-2 deficient mice: a new model to study autoimmunity and self-tolerance.
    Immunol Rev. 1995 Dec;148:35-44 PMID: 8825281
  58. CD4+ T cell help impairs CD8+ T cell deletion induced by cross-presentation of self-antigens and favors autoimmunity.
    J Exp Med. 1997 Dec 15;186(12):2057-62 PMID: 9396776
  59. Cloning, expression and tissue distribution of the murine homologue of the melanocyte lineage-specific antigen gp100.
    Melanoma Res. 1997 Dec;7(6):463-70 PMID: 9464618
  60. CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells.
    J Immunol. 1998 Feb 1;160(3):1212-8 PMID: 9570536
  61. Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency.
    Int Immunol. 1998 Apr;10(4):371-8 PMID: 9620592
Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
0022-1767
DOI
10.4049/jimmunol.174.5.2591
Email
[email protected]
Published
2005-03-01
Pages
2591-601
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC1403291
Subset
IM
Grants
Intramural NIH HHS · Z01 BC010763-01 · United States
Intramural NIH HHS · Z01 SC003811-32 · United States
Intramural NIH HHS · Z99 CA999999 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.174.5.2591 PMC Full Text View journal details
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