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PMID: 17452521 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural

Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity.

The Journal of experimental medicine ·Vol. 204 ·No. 5 ·2007-05-14 ·Pages 1119-30

Boos MD, Yokota Y, Eberl G, Kee BL

Abstract

The Id2 transcriptional repressor is essential for development of natural killer (NK) cells, lymphoid tissue-inducing (LTi) cells, and secondary lymphoid tissues. Id2 was proposed to regulate NK and LTi lineage specification from multipotent progenitors through suppression of E proteins. We report that NK cell progenitors are not reduced in the bone marrow (BM) of Id2(-/-) mice, demonstrating that Id2 is not essential for NK lineage specification. Rather, Id2 is required for development of mature (m) NK cells. We define the mechanism by which Id2 functions by showing that a reduction in E protein activity, through deletion of E2A, overcomes the need for Id2 in development of BM mNK cells, LTi cells, and secondary lymphoid tissues. However, mNK cells are not restored in the blood or spleen of Id2(-/-)E2A(-/-) mice, suggesting a role for Id2 in suppression of alternative E proteins after maturation. Interestingly, the few splenic mNK cells in Id2(-/-) and Id2(-/-)E2A(-/-) mice have characteristics of thymus-derived NK cells, which develop in the absence of Id2, implying a differential requirement for Id2 in BM and thymic mNK development. Our findings redefine the essential functions of Id2 in lymphoid development and provide insight into the dynamic regulation of E and Id proteins during this process.

MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/genetics,immunology Cell Differentiation/immunology Cell Lineage/immunology DNA Primers Flow Cytometry Gene Expression Regulation/immunology Genotype Inhibitor of Differentiation Protein 2/genetics,immunology Killer Cells, Natural/immunology Lymphoid Tissue/immunology Mice Mice, Knockout Microscopy, Fluorescence Polymerase Chain Reaction
Chemicals
Basic Helix-Loop-Helix Transcription Factors DNA Primers Idb2 protein, mouse Inhibitor of Differentiation Protein 2 Tcf3 protein, mouse
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Boos Markus D
Committee on Immunology, University of Chicago, Chicago, IL 60657, USA.
Yokota Yoshifumi
Eberl Gerard
Kee Barbara L
References (54)
54 references, click to expand
  1. Interleukin (IL)-15R[alpha]-deficient natural killer cells survive in normal but not IL-15R[alpha]-deficient mice.
    J Exp Med. 2003 Apr 21;197(8):977-84 PMID: 12695489
  2. Organogenesis of lymphoid tissues.
    Nat Rev Immunol. 2003 Apr;3(4):292-303 PMID: 12669020
  3. Commitment of common T/Natural killer (NK) progenitors to unipotent T and NK progenitors in the murine fetal thymus revealed by a single progenitor assay.
    J Exp Med. 1999 Dec 6;190(11):1617-26 PMID: 10587352
  4. An essential function for the nuclear receptor RORgamma(t) in the generation of fetal lymphoid tissue inducer cells.
    Nat Immunol. 2004 Jan;5(1):64-73 PMID: 14691482
  5. Acquisition of MHC-specific receptors on murine natural killer cells.
    Crit Rev Immunol. 2003;23(4):251-66 PMID: 14700270
  6. The dynamic life of natural killer cells.
    Annu Rev Immunol. 2004;22:405-29 PMID: 15032583
  7. Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A.
    J Exp Med. 2004 Jun 21;199(12):1689-700 PMID: 15210745
  8. Coordinate expression and trans presentation of interleukin (IL)-15Ralpha and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis.
    J Exp Med. 2004 Oct 4;200(7):825-34 PMID: 15452177
  9. An inhibitory domain of E12 transcription factor prevents DNA binding in E12 homodimers but not in E12 heterodimers.
    Cell. 1991 Jan 25;64(2):459-70 PMID: 1846322
  10. Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins.
    Mol Cell Biol. 1991 Nov;11(11):5603-11 PMID: 1922066
  11. A population of early fetal thymocytes expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells.
    Cell. 1992 Apr 3;69(1):139-50 PMID: 1532536
  12. The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein.
    Genes Dev. 1994 Jun 1;8(11):1270-84 PMID: 7926730
  13. The helix-loop-helix gene E2A is required for B cell formation.
    Cell. 1994 Dec 2;79(5):875-84 PMID: 8001124
  14. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements.
    Cell. 1994 Dec 2;79(5):885-92 PMID: 8001125
  15. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain.
    Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):377-81 PMID: 7831294
  16. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain.
    Immunity. 1995 Mar;2(3):223-38 PMID: 7697543
  17. Helix-loop-helix proteins LYL1 and E2a form heterodimeric complexes with distinctive DNA-binding properties in hematolymphoid cells.
    Mol Cell Biol. 1996 May;16(5):2394-401 PMID: 8628307
  18. Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain.
    J Exp Med. 1997 Feb 3;185(3):499-505 PMID: 9053450
  19. Identification of a novel developmental stage marking lineage commitment of progenitor thymocytes.
    J Exp Med. 1997 Jul 21;186(2):173-82 PMID: 9221746
  20. Differential interactions of Id proteins with basic-helix-loop-helix transcription factors.
    J Biol Chem. 1997 Aug 8;272(32):19785-93 PMID: 9242638
  21. Inhibition of T cell and promotion of natural killer cell development by the dominant negative helix loop helix factor Id3.
    J Exp Med. 1997 Nov 3;186(9):1597-602 PMID: 9348318
  22. Identification of clonogenic common lymphoid progenitors in mouse bone marrow.
    Cell. 1997 Nov 28;91(5):661-72 PMID: 9393859
  23. The Ets-1 transcription factor is required for the development of natural killer cells in mice.
    Immunity. 1998 Oct;9(4):555-63 PMID: 9806641
  24. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation.
    Immunity. 1998 Nov;9(5):669-76 PMID: 9846488
  25. Lineage commitment and differentiation of T and natural killer lymphocytes in the fetal mouse.
    Immunol Rev. 1998 Oct;165:63-74 PMID: 9850852
  26. Ectopic expression of E47 or E12 promotes the death of E2A-deficient lymphomas.
    Proc Natl Acad Sci U S A. 1999 Feb 2;96(3):996-1001 PMID: 9927682
  27. Development of peripheral lymphoid organs and natural killer cells depends on the helix-loop-helix inhibitor Id2.
    Nature. 1999 Feb 25;397(6721):702-6 PMID: 10067894
  28. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5.
    Nature. 1999 Oct 7;401(6753):556-62 PMID: 10524622
  29. Cellular interactions in lymph node development.
    J Immunol. 2005 Jan 1;174(1):21-5 PMID: 15611222
  30. Retinoblastoma promotes definitive erythropoiesis by repressing Id2 in fetal liver macrophages.
    Nature. 2004 Dec 23;432(7020):1040-5 PMID: 15616565
  31. Roles for common cytokine receptor gamma-chain-dependent cytokines in the generation, differentiation, and maturation of NK cell precursors and peripheral NK cells in vivo.
    J Immunol. 2005 Feb 1;174(3):1213-21 PMID: 15661875
  32. Id3 induces growth arrest and caspase-2-dependent apoptosis in B lymphocyte progenitors.
    J Immunol. 2005 Oct 1;175(7):4518-27 PMID: 16177095
  33. The earliest thymic progenitors in adults are restricted to T, NK, and dendritic cell lineage and have a potential to form more diverse TCRbeta chains than fetal progenitors.
    J Immunol. 2005 Nov 1;175(9):5848-56 PMID: 16237077
  34. Strategies of natural killer cell recognition and signaling.
    Curr Top Microbiol Immunol. 2006;298:1-21 PMID: 16329183
  35. The CD2 family of natural killer cell receptors.
    Curr Top Microbiol Immunol. 2006;298:91-120 PMID: 16323413
  36. NK cell recognition of mouse cytomegalovirus-infected cells.
    Curr Top Microbiol Immunol. 2006;298:183-206 PMID: 16329187
  37. Helix-loop-helix proteins in lymphocyte lineage determination.
    Curr Top Microbiol Immunol. 2005;290:15-27 PMID: 16480037
  38. Natural killer cell developmental pathways: a question of balance.
    Annu Rev Immunol. 2006;24:257-86 PMID: 16551250
  39. A thymic pathway of mouse natural killer cell development characterized by expression of GATA-3 and CD127.
    Nat Immunol. 2006 Nov;7(11):1217-24 PMID: 17013389
  40. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice.
    J Exp Med. 2000 Mar 6;191(5):771-80 PMID: 10704459
  41. A chemokine-driven positive feedback loop organizes lymphoid follicles.
    Nature. 2000 Jul 20;406(6793):309-14 PMID: 10917533
  42. Id2 is a retinoblastoma protein target and mediates signalling by Myc oncoproteins.
    Nature. 2000 Oct 5;407(6804):592-8 PMID: 11034201
  43. The helix-loop-helix inhibitor Id2 and cell differentiation control.
    Curr Top Microbiol Immunol. 2000;251:35-41 PMID: 11036756
  44. Id2 and Id3 inhibit development of CD34(+) stem cells into predendritic cell (pre-DC)2 but not into pre-DC1. Evidence for a lymphoid origin of pre-DC2.
    J Exp Med. 2000 Dec 18;192(12):1775-84 PMID: 11120774
  45. Differential requirement for the transcription factor PU.1 in the generation of natural killer cells versus B and T cells.
    Blood. 2001 May 1;97(9):2625-32 PMID: 11313251
  46. Commitment to natural killer cells requires the helix-loop-helix inhibitor Id2.
    Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5164-9 PMID: 11296270
  47. The fetal liver counterpart of adult common lymphoid progenitors gives rise to all lymphoid lineages, CD45+CD4+CD3- cells, as well as macrophages.
    J Immunol. 2001 Jun 1;166(11):6593-601 PMID: 11359812
  48. Identification of committed NK cell progenitors in adult murine bone marrow.
    Eur J Immunol. 2001 Jun;31(6):1900-9 PMID: 11433387
  49. In vivo developmental stages in murine natural killer cell maturation.
    Nat Immunol. 2002 Jun;3(6):523-8 PMID: 12006976
  50. Initiation of NALT organogenesis is independent of the IL-7R, LTbetaR, and NIK signaling pathways but requires the Id2 gene and CD3(-)CD4(+)CD45(+) cells.
    Immunity. 2002 Jul;17(1):31-40 PMID: 12150889
  51. The ETS protein MEF plays a critical role in perforin gene expression and the development of natural killer and NK-T cells.
    Immunity. 2002 Oct;17(4):437-49 PMID: 12387738
  52. Relationships between early B- and NK-lineage lymphocyte precursors in bone marrow.
    Blood. 2002 Nov 15;100(10):3672-80 PMID: 12393656
  53. Murine natural killer cell progenitors and their requirements for development.
    Semin Immunol. 2002 Dec;14(6):453-60 PMID: 12457618
  54. Regulation of TCF ETS-domain transcription factors by helix-loop-helix motifs.
    Nucleic Acids Res. 2003 Aug 15;31(16):4717-28 PMID: 12907712
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20061959
Published
2007-05-14
Epub
2007-00-23
Pages
1119-30
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118569
Subset
IM
Grants
NCI NIH HHS · R01 CA099978 · United States
NCI NIH HHS · R01 CA99978 · United States
External Links
PubMed source DOI: 10.1084/jem.20061959 PMC Full Text View journal details
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