Home LiteratureArticle Details
PMID: 20181882 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 184 ·No. 7 ·2010-04-01 ·Pages 3433-41

Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM

Abstract

Helios, a member of the Ikaros transcription factor family, is preferentially expressed at the mRNA level by regulatory T cells (Treg cells). We evaluated Helios protein expression using a newly generated mAb and demonstrated that it is expressed in all thymocytes at the double negative 2 stage of thymic development. Although Helios was expressed by 100% of CD4(+)CD8(-)Foxp3(+) thymocytes, its expression in peripheral lymphoid tissues was restricted to a subpopulation ( approximately 70%) of Foxp3(+) T cells in mice and humans. Neither mouse nor human naive T cells induced to express Foxp3 in vitro by TCR stimulation in the presence of TGF-beta expressed Helios. Ag-specific Foxp3(+) T cells induced in vivo by Ag feeding also failed to express Helios. Collectively, these results demonstrate that Helios is potentially a specific marker of thymic-derived Treg cells and raises the possibility that a significant percentage of Foxp3(+) Treg cells are generated extrathymically.

MeSH Terms
Animals Cell Differentiation/immunology Cell Lineage Cell Separation DNA-Binding Proteins/biosynthesis,immunology Female Flow Cytometry Forkhead Transcription Factors/immunology,metabolism Humans Ikaros Transcription Factor/biosynthesis,immunology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Reverse Transcriptase Polymerase Chain Reaction Spleen/cytology,immunology T-Lymphocyte Subsets/cytology,immunology,metabolism T-Lymphocytes, Regulatory/cytology,immunology,metabolism Thymus Gland/cytology,immunology Transcription Factors/biosynthesis,immunology
Chemicals
DNA-Binding Proteins FOXP3 protein, human Forkhead Transcription Factors Foxp3 protein, mouse IKZF2 protein, human Transcription Factors Zfpn1a2 protein, mouse Ikaros Transcription Factor
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Thornton Angela M
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Korty Patricia E
Tran Dat Q
Wohlfert Elizabeth A
Murray Patrick E
Belkaid Yasmine
Shevach Ethan M
References (46)
46 references, click to expand
  1. In vivo instruction of suppressor commitment in naive T cells.
    J Exp Med. 2004 May 17;199(10):1401-8 PMID: 15148338
  2. Cutting edge: regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta.
    J Immunol. 2007 Jun 1;178(11):6725-9 PMID: 17513718
  3. The Ikaros gene is required for the development of all lymphoid lineages.
    Cell. 1994 Oct 7;79(1):143-56 PMID: 7923373
  4. Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis.
    Int Immunol. 2006 Aug;18(8):1197-209 PMID: 16772372
  5. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype.
    Blood. 2007 Oct 15;110(8):2983-90 PMID: 17644734
  6. Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells.
    Immunity. 2006 Aug;25(2):249-59 PMID: 16879995
  7. Ikaros-family proteins: in search of molecular functions during lymphocyte development.
    Curr Top Microbiol Immunol. 2005;290:29-47 PMID: 16480038
  8. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production.
    Int Immunol. 2007 Apr;19(4):345-54 PMID: 17329235
  9. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors.
    Immunity. 2004 Aug;21(2):267-77 PMID: 15308106
  10. Aiolos regulates B cell activation and maturation to effector state.
    Immunity. 1998 Oct;9(4):543-53 PMID: 9806640
  11. A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma.
    Cell. 1995 Oct 20;83(2):289-99 PMID: 7585946
  12. Back to the thymus: peripheral T cells come home.
    Immunol Cell Biol. 2009 Jan;87(1):58-64 PMID: 19030016
  13. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
    Nature. 2006 May 11;441(7090):235-8 PMID: 16648838
  14. Inducing and expanding regulatory T cell populations by foreign antigen.
    Nat Immunol. 2005 Dec;6(12):1219-27 PMID: 16244650
  15. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo.
    Nat Immunol. 2009 Sep;10(9):1000-7 PMID: 19633673
  16. Ikaros enforces the costimulatory requirement for IL2 gene expression and is required for anergy induction in CD4+ T lymphocytes.
    J Immunol. 2007 Dec 1;179(11):7305-15 PMID: 18025173
  17. Oral tolerance in the absence of naturally occurring Tregs.
    J Clin Invest. 2005 Jul;115(7):1923-33 PMID: 15937545
  18. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells.
    Nature. 2007 Feb 22;445(7130):936-40 PMID: 17237761
  19. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3.
    Nat Genet. 2001 Jan;27(1):20-1 PMID: 11137993
  20. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.
    Immunity. 2008 Jul 18;29(1):44-56 PMID: 18585065
  21. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?
    Immunity. 2009 May;30(5):626-35 PMID: 19464985
  22. Helios deficiency has minimal impact on T cell development and function.
    J Immunol. 2009 Aug 15;183(4):2303-11 PMID: 19620299
  23. Activation requirements for the induction of CD4+CD25+ T cell suppressor function.
    Eur J Immunol. 2004 Feb;34(2):366-76 PMID: 14768041
  24. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells.
    Science. 2009 Aug 28;325(5944):1142-6 PMID: 19696312
  25. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid.
    J Exp Med. 2007 Aug 6;204(8):1775-85 PMID: 17620362
  26. Helios, a novel dimerization partner of Ikaros expressed in the earliest hematopoietic progenitors.
    Curr Biol. 1998 Apr 23;8(9):508-15 PMID: 9560339
  27. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity.
    Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1903-8 PMID: 19174509
  28. Antigen-specific peripheral shaping of the natural regulatory T cell population.
    J Exp Med. 2008 Dec 22;205(13):3105-17 PMID: 19064700
  29. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities.
    Immunol Rev. 2008 Jun;223:371-90 PMID: 18613848
  30. A two-step process for thymic regulatory T cell development.
    Immunity. 2008 Jan;28(1):100-11 PMID: 18199417
  31. Subtractive cloning: new genes for studying inflammatory disorders.
    Ann Periodontol. 2002 Dec;7(1):17-28 PMID: 16013213
  32. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature.
    Immunity. 2007 Nov;27(5):786-800 PMID: 18024188
  33. Aiolos, a lymphoid restricted transcription factor that interacts with Ikaros to regulate lymphocyte differentiation.
    EMBO J. 1997 Apr 15;16(8):2004-13 PMID: 9155026
  34. Effects of cyclosporine on transplant tolerance: the role of IL-2.
    Am J Transplant. 2007 Aug;7(8):1907-16 PMID: 17617853
  35. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy.
    Nat Genet. 2001 Jan;27(1):18-20 PMID: 11137992
  36. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation.
    Immunity. 1996 Dec;5(6):537-49 PMID: 8986714
  37. Control of regulatory T cell lineage commitment and maintenance.
    Immunity. 2009 May;30(5):616-25 PMID: 19464984
  38. Regulatory T cell development in the absence of functional Foxp3.
    Nat Immunol. 2007 Apr;8(4):359-68 PMID: 17273171
  39. Mechanisms of foxp3+ T regulatory cell-mediated suppression.
    Immunity. 2009 May;30(5):636-45 PMID: 19464986
  40. Distinct subsets of FoxP3+ regulatory T cells participate in the control of immune responses.
    J Immunol. 2007 Jun 1;178(11):6901-11 PMID: 17513739
  41. Foxp3-dependent programme of regulatory T-cell differentiation.
    Nature. 2007 Feb 15;445(7129):771-5 PMID: 17220874
  42. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells.
    J Immunol. 2007 Jun 1;178(11):7032-41 PMID: 17513752
  43. Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes.
    Immunity. 1999 Mar;10(3):345-55 PMID: 10204490
  44. A key role for TGF-beta signaling to T cells in the long-term acceptance of allografts.
    J Immunol. 2007 Sep 15;179(6):3648-54 PMID: 17785800
  45. Predominant interaction of both Ikaros and Helios with the NuRD complex in immature thymocytes.
    J Biol Chem. 2007 Oct 12;282(41):30227-38 PMID: 17681952
  46. Helios, a T cell-restricted Ikaros family member that quantitatively associates with Ikaros at centromeric heterochromatin.
    Genes Dev. 1998 Mar 15;12(6):782-96 PMID: 9512513
Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.0904028
Published
2010-04-01
Epub
2010-00-24
Pages
3433-41
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC3725574
Subset
IM
Grants
Intramural NIH HHS · ZIA AI000959-04 · United States
Corrections
CommentIn
PMID: 21127313
External Links
PubMed source DOI: 10.4049/jimmunol.0904028 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