Home LiteratureArticle Details
PMID: 10899916 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation.

The Journal of experimental medicine ·Vol. 192 ·No. 2 ·2000-07-17 ·Pages 295-302

Read S, Malmström V, Powrie F

Abstract

It is now clear that functionally specialized regulatory T (Treg) cells exist as part of the normal immune repertoire, preventing the development of pathogenic responses to both self- and intestinal antigens. Here, we report that the Treg cells that control intestinal inflammation express the same phenotype (CD25(+)CD45RB(low)CD4(+)) as those that control autoimmunity. Previous studies have failed to identify how CD25(+) Treg cells function in vivo. Our studies reveal that the immune-suppressive function of these cells in vivo is dependent on signaling via the negative regulator of T cell activation cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as secretion of the immune-suppressive cytokine transforming growth factor beta. Strikingly, constitutive expression of CTLA-4 among CD4(+) cells was restricted primarily to Treg cells, suggesting that CTLA-4 expression by these cells is involved in their immune-suppressive function. These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling. Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.

MeSH Terms
Abatacept Animals Antigens, CD Antigens, Differentiation/analysis,physiology CD4-Positive T-Lymphocytes/physiology CTLA-4 Antigen Colitis/prevention & control Immunoconjugates Leukocyte Common Antigens/analysis Mice Mice, Inbred BALB C Mice, Inbred C57BL Receptors, Interleukin-2/analysis T-Lymphocytes, Regulatory/physiology Transforming Growth Factor beta/physiology
Chemicals
Antigens, CD Antigens, Differentiation CTLA-4 Antigen Ctla4 protein, mouse Immunoconjugates Receptors, Interleukin-2 Transforming Growth Factor beta Abatacept Leukocyte Common Antigens
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Read S
Oxford University, Nuffield Department of Surgery, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
Malmström V
Powrie F
References (46)
46 references, click to expand
  1. From synapses to immunological memory: the role of sustained T cell stimulation.
    Curr Opin Immunol. 2000 Feb;12(1):92-8 PMID: 10679412
  2. An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation.
    J Exp Med. 1999 Oct 4;190(7):995-1004 PMID: 10510089
  3. The immune response of germ-free piglets after peroral monocontamination with living Escherichia coli strain 086. I. The fate of antigen, dynamics and site of antibody formation, nature of antibodies and formation of heterohaemagglutinins.
    Folia Biol (Praha). 1970 Jun;16(3):177-87 PMID: 4914735
  4. Surface antigen expression and immunoglobulin gene rearrangement during mouse pre-B cell development.
    Immunol Rev. 1982;69:5-23 PMID: 6984001
  5. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease.
    J Exp Med. 1985 Jan 1;161(1):72-87 PMID: 3871469
  6. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential.
    J Exp Med. 1993 Mar 1;177(3):627-36 PMID: 8094734
  7. CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells.
    J Exp Med. 1993 Jul 1;178(1):237-44 PMID: 8100269
  8. Differential T cell costimulatory requirements in CD28-deficient mice.
    Science. 1993 Jul 30;261(5121):609-12 PMID: 7688139
  9. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice.
    Int Immunol. 1993 Nov;5(11):1461-71 PMID: 7903159
  10. The B7 and CD28 receptor families.
    Immunol Today. 1994 Jul;15(7):321-31 PMID: 7522010
  11. CD28-B7 interactions in T-cell activation.
    Curr Opin Immunol. 1994 Jun;6(3):414-9 PMID: 7522466
  12. CTLA-4 can function as a negative regulator of T cell activation.
    Immunity. 1994 Aug;1(5):405-13 PMID: 7882171
  13. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.
    Immunity. 1994 Oct;1(7):553-62 PMID: 7600284
  14. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation.
    J Exp Med. 1995 Aug 1;182(2):459-65 PMID: 7543139
  15. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases.
    J Immunol. 1995 Aug 1;155(3):1151-64 PMID: 7636184
  16. T cells in inflammatory bowel disease: protective and pathogenic roles.
    Immunity. 1995 Aug;3(2):171-4 PMID: 7648390
  17. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.
    Science. 1995 Nov 10;270(5238):985-8 PMID: 7481803
  18. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.
    Immunity. 1995 Nov;3(5):541-7 PMID: 7584144
  19. Enhancement of antitumor immunity by CTLA-4 blockade.
    Science. 1996 Mar 22;271(5256):1734-6 PMID: 8596936
  20. Inflammatory bowel disease in C.B-17 scid mice reconstituted with the CD45RBhigh subset of CD4+ T cells.
    Am J Pathol. 1996 May;148(5):1503-15 PMID: 8623920
  21. Intracellular trafficking of CTLA-4 and focal localization towards sites of TCR engagement.
    Immunity. 1996 Jun;4(6):535-43 PMID: 8673700
  22. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells.
    J Exp Med. 1996 Jun 1;183(6):2533-40 PMID: 8676074
  23. CTLA-4 ligation blocks CD28-dependent T cell activation.
    J Exp Med. 1996 Jun 1;183(6):2541-50 PMID: 8676075
  24. A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells.
    J Exp Med. 1996 Jun 1;183(6):2669-74 PMID: 8676088
  25. CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis.
    J Immunol. 1996 Aug 15;157(4):1333-6 PMID: 8759711
  26. 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
  27. CTLA-4: a negative regulator of autoimmune disease.
    J Exp Med. 1996 Aug 1;184(2):783-8 PMID: 8760834
  28. The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset.
    Immunol Rev. 1996 Feb;149:195-216 PMID: 9005215
  29. Regulation of surface and intracellular expression of CTLA4 on mouse T cells.
    J Immunol. 1996 Dec 1;157(11):4762-70 PMID: 8943377
  30. Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients.
    J Immunol. 1997 Apr 1;158(7):3464-73 PMID: 9120308
  31. Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement.
    Immunity. 1997 Apr;6(4):411-7 PMID: 9133420
  32. Protective immunity to nematode infection is induced by CTLA-4 blockade.
    J Exp Med. 1997 Jul 21;186(2):183-7 PMID: 9221747
  33. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes.
    J Exp Med. 1998 Feb 2;187(3):427-32 PMID: 9449722
  34. Homeostasis and self-tolerance in the immune system: turning lymphocytes off.
    Science. 1998 Apr 10;280(5361):243-8 PMID: 9535647
  35. 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
  36. CD4+ T-cells in the regulation of inflammatory responses in the intestine.
    Res Immunol. 1997 Oct-Dec;148(8-9):576-81 PMID: 9588837
  37. 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
  38. 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. 1998 Nov 16;188(10):1849-57 PMID: 9815262
  39. CD38+ CD45RB(low) CD4+ T cells: a population of T cells with immune regulatory activities in vitro.
    Eur J Immunol. 1998 Nov;28(11):3435-47 PMID: 9842886
  40. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.
    Int Immunol. 1998 Dec;10(12):1969-80 PMID: 9885918
  41. Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC- cells and CD4(+)CD8(-) thymocytes.
    J Exp Med. 1999 Jan 18;189(2):279-88 PMID: 9892610
  42. Costimulatory regulation of T cell function.
    Curr Opin Cell Biol. 1999 Apr;11(2):203-10 PMID: 10209159
  43. Phenotypic analysis of CTLA-4 and CD28 expression during transient peptide-induced T cell activation in vivo.
    Int Immunol. 1999 May;11(5):667-75 PMID: 10330272
  44. Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous.
    J Immunol. 1999 Aug 1;163(3):1128-31 PMID: 10415006
  45. The role of CTLA-4 in regulating Th2 differentiation.
    J Immunol. 1999 Sep 1;163(5):2634-9 PMID: 10453003
  46. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4.
    J Exp Med. 2000 Jul 17;192(2):303-10 PMID: 10899917
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.192.2.295
Published
2000-07-17
Pages
295-302
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2193261
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.192.2.295 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2