Skip to main content
SpringerLink
Log in

Notch2 and Immune Function

  • Chapter
  • First Online:
Book cover Notch Regulation of the Immune System

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 360))

Abstract

Notch2 is expressed in many cell types of most lineages in the hematolymphoid compartment and has specific roles in differentiation and function of various immune cells. Notch2 is required for development of splenic marginal zone B cells and regulates differentiation of dendritic cells (DCs) in the spleen. Notch2 appears to play some specific roles in the intestinal immunity, given that the fate of mast cells and a subset of DCs is regulated by Notch2 in the intestine. Notch2 also has important roles in helper T cell divergence from naïve CD4 T cells and activation of cytotoxic T cells. Moreover, recent genetic evidence suggests that both gain-and loss-of-function abnormalities of Notch2 cause transformation of immune cells. Inactivating mutations are found in Notch2 signaling pathways in chronic myelomonocytic leukemia, while activating mutations are found in mature B cell lymphomas, which reflects the role of Notch2 in the developmental process of these cells.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA (2004) Instruction of distinct CD4 T helper cell fates by different notch ligands on antigen-presenting cells. Cell 117(4):515–526

    Article  PubMed  CAS  Google Scholar 

  • Amsen D, Antov A, Jankovic D et al (2007) Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 27(1):89–99

    Article  PubMed  CAS  Google Scholar 

  • Bogunovic M, Ginhoux F, Helft J et al (2009) Origin of the lamina propria dendritic cell network. Immunity 31(3):513–525

    Article  PubMed  CAS  Google Scholar 

  • Caton ML, Smith-Raska MR, Reizis B (2007) Notch-RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen. J Exp Med 204(7):1653–1664

    PubMed  CAS  Google Scholar 

  • Cho OH, Shin HM, Miele L et al (2009) Notch regulates cytolytic effector function in CD8+ T cells. J Immunol 182(6):3380–3389

    Article  PubMed  CAS  Google Scholar 

  • den Haan JM, Lehar SM, Bevan MJ (2000) CD8(+) but not CD8(−) dendritic cells cross-prime cytotoxic T cells in vivo. J Exp Med 192(12):1685–1696

    Article  Google Scholar 

  • Denning TL, Norris BA, Medina-Contreras O et al (2011) Functional specializations of intestinal dendritic cell and macrophage subsets that control Th17 and regulatory T cell responses are dependent on the T cell/APC ratio, source of mouse strain, and regional localization. J Immunol 187(2):733–747

    Article  PubMed  CAS  Google Scholar 

  • Dudziak D, Kamphorst AO, Heidkamp GF et al (2007) Differential antigen processing by dendritic cell subsets in vivo. Science 315(5808):107–111

    Article  PubMed  CAS  Google Scholar 

  • Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC, Pear WS (2007) Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27(1):100–110

    Article  PubMed  CAS  Google Scholar 

  • Fu L, Kogoshi H, Nara N, Tohda S (2006) NOTCH1 mutations are rare in acute myeloid leukemia. Leuk Lymphoma 47(11):2400–2403

    Article  PubMed  CAS  Google Scholar 

  • Galli SJ, Nakae S, Tsai M (2005) Mast cells in the development of adaptive immune responses. Nat Immunol 6(2):135–142

    Article  PubMed  CAS  Google Scholar 

  • Gibb DR, El Shikh M, Kang DJ et al (2010) ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo. J Exp Med 207(3):623–635

    Article  PubMed  CAS  Google Scholar 

  • Gurish MF, Boyce JA (2006) Mast cells: ontogeny, homing, and recruitment of a unique innate effector cell. J Allergy Clin Immunol 117(6):1285–1291

    Article  PubMed  CAS  Google Scholar 

  • Hozumi K, Negishi N, Suzuki D et al (2004) Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat Immunol 5(6):638–644

    Article  PubMed  CAS  Google Scholar 

  • Karanu FN et al. (2000) The notch ligand Jagged-1 represents a novel growth factor of human hematopoietic stem cells. JEM 192 (9) 1365–1372

    Article  CAS  Google Scholar 

  • Kannan S, Fang W, Song G et al (2011) Notch/HES1-mediated PARP1 activation: a cell type-specific mechanism for tumor suppression. Blood 117(10):2891–2900

    Article  PubMed  CAS  Google Scholar 

  • Klinakis A, Lobry C, Abdel-Wahab O et al (2011) A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473(7346):230–233

    Article  PubMed  CAS  Google Scholar 

  • Kridel R, Meissner B, Rogic S et al (2012) Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 119(9):1963–1971

    Article  PubMed  CAS  Google Scholar 

  • Kunisato A, Chiba S, Nakagami-Yamaguchi E et al (2003) HES-1 preserves purified hematopoietic stem cells ex vivo and accumulates side population cells in vivo. Blood 101(5):1777–1783

    Article  PubMed  CAS  Google Scholar 

  • Kuroda K, Han H, Tani S et al (2003) Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18(2):301–312

    Article  PubMed  CAS  Google Scholar 

  • Lee SY, Kumano K, Nakazaki K et al (2009) Gain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphoma. Cancer Sci 100(5):920–926

    Article  PubMed  CAS  Google Scholar 

  • Lewis KL, Caton ML, Bogunovic M et al (2011) Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35(5):780–791

    Article  PubMed  CAS  Google Scholar 

  • Loder F, Mutschler B, Ray RJ et al (1999) B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J Exp Med 190(1):75–89

    Article  PubMed  CAS  Google Scholar 

  • Maekawa Y, Tsukumo S, Chiba S et al (2003) Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells. Immunity 19(4):549–559

    Article  PubMed  CAS  Google Scholar 

  • Maekawa Y, Minato Y, Ishifune C et al (2008) Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity. Nat Immunol 9(10):1140–1147

    Article  PubMed  CAS  Google Scholar 

  • Maillard I, Koch U, Dumortier A et al (2008) Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2(4):356–366

    Article  PubMed  CAS  Google Scholar 

  • Mancini SJ, Mantei N, Dumortier A, Suter U, MacDonald HR, Radtke F (2005) Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 105(6):2340–2342

    Article  PubMed  CAS  Google Scholar 

  • Martin F, Kearney JF (2002) Marginal-zone B cells. Nat Rev Immunol 2(5):323–335

    Article  PubMed  CAS  Google Scholar 

  • Maruyama H, Yabu Y, Yoshida A, Nawa Y, Ohta N (2000) A role of mast cell glycosaminoglycans for the immunological expulsion of intestinal nematode, Strongyloides venezuelensis. J Immunol 164(7):3749–3754

    PubMed  CAS  Google Scholar 

  • Miller HR, Pemberton AD (2002) Tissue-specific expression of mast cell granule serine proteinases and their role in inflammation in the lung and gut. Immunology 105(4):375–390

    Article  PubMed  CAS  Google Scholar 

  • Ohishi K et al. (2002) Delta-1 enhances marrow and thymus repopulating ability of human CD34(+)CD38(-) cord blood cells. J Clin Invest 110(8):1165−1174

    PubMed  CAS  Google Scholar 

  • Oyama T, Harigaya K, Muradil A et al (2007) Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo. Proc Natl Acad Sci USA 104(23):9764–9769

    Article  PubMed  CAS  Google Scholar 

  • Puente XS, Pinyol M, Quesada V et al (2011) Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 475(7354):101–105

    Article  PubMed  CAS  Google Scholar 

  • Radtke F, Wilson A, Stark G et al (1999) Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10(5):547–558

    Article  PubMed  CAS  Google Scholar 

  • Saito T, Chiba S, Ichikawa M et al (2003) Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18(5):675–685

    Article  PubMed  CAS  Google Scholar 

  • Sakata-Yanagimoto M, Nakagami-Yamaguchi E, Saito T et al (2008) Coordinated regulation of transcription factors through Notch2 is an important mediator of mast cell fate. Proc Natl Acad Sci USA 105(22):7839–7844

    Article  PubMed  CAS  Google Scholar 

  • Sakata-Yanagimoto M, Sakai T, Miyake Y et al (2011) Notch2 signaling is required for proper mast cell distribution and mucosal immunity in the intestine. Blood 117(1):128–134

    Article  PubMed  CAS  Google Scholar 

  • Sheng Y, Yahata T, Negishi N et al (2008) Expression of Delta-like 1 in the splenic non-hematopoietic cells is essential for marginal zone B cell development. Immunol Lett 121(1):33–37

    Article  PubMed  CAS  Google Scholar 

  • Song R, Kim YW, Koo BK et al (2008) Mind bomb 1 in the lymphopoietic niches is essential for T and marginal zone B cell development. J Exp Med 205(11):2525–2536

    Article  PubMed  CAS  Google Scholar 

  • Steinman RM, Idoyaga J (2010) Features of the dendritic cell lineage. Immunol Rev 234(1):5–17

    Article  PubMed  CAS  Google Scholar 

  • Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT (2002) Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 99(7):2369–2378

    Article  PubMed  CAS  Google Scholar 

  • Sugimoto K, Maekawa Y, Kitamura A et al (2010) Notch2 signaling is required for potent antitumor immunity in vivo. J Immunol 184(9):4673–4678

    Article  PubMed  CAS  Google Scholar 

  • Sun J, Krawczyk CJ, Pearce EJ (2008) Suppression of Th2 cell development by Notch ligands Delta1 and Delta4. J Immunol 180(3):1655–1661

    PubMed  CAS  Google Scholar 

  • Suluki T et al. (2006) Highly efficient ex vivo expansion of human hematopoietic stem cells using Delta1-Fc chimeric protein. Stem Cells 24(11):2456–2465

    Article  Google Scholar 

  • Tan JB, Xu K, Cretegny K et al (2009) Lunatic and manic fringe cooperatively enhance marginal zone B cell precursor competition for delta-like 1 in splenic endothelial niches. Immunity 30(2):254–263

    Article  PubMed  Google Scholar 

  • Tanigaki K, Han H, Yamamoto N et al (2002) Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nat Immunol 3(5):443–450

    Article  PubMed  CAS  Google Scholar 

  • Troen G, Wlodarska I, Warsame A, Hernandez Llodra S, De Wolf-Peeters C, Delabie J (2008) NOTCH2 mutations in marginal zone lymphoma. Haematologica 93(7):1107–1109

    Article  PubMed  Google Scholar 

  • Tu L, Fang TC, Artis D et al (2005) Notch signaling is an important regulator of type 2 immunity. J Exp Med 202(8):1037–1042

    Article  PubMed  CAS  Google Scholar 

  • Varnum-Finney B, Xu L, Brashem-Stein C et al (2000) Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med 6(11):1278–1281

    Article  PubMed  CAS  Google Scholar 

  • Varnum-Finney B, Halasz LM, Sun M, Gridley T, Radtke F, Bernstein ID (2011) Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells. J Clin Invest 121(3):1207–1216

    Article  PubMed  CAS  Google Scholar 

  • Weng AP, Ferrando AA, Lee W et al (2004) Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306(5694):269–271

    Article  PubMed  CAS  Google Scholar 

  • Wouters BJ, Jorda MA, Keeshan K et al (2007) Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood 110(10):3706–3714

    Article  PubMed  CAS  Google Scholar 

  • Wu L, Maillard I, Nakamura M, Pear WS, Griffin JD (2007) The transcriptional coactivator Maml1 is required for Notch2-mediated marginal zone B-cell development. Blood 110(10):3618–3623

    Article  PubMed  CAS  Google Scholar 

  • Zweidler-McKay PA, He Y, Xu L et al (2005) Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood 106(12):3898–3906

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan

    Mamiko Sakata-Yanagimoto & Shigeru Chiba

Authors
  1. Mamiko Sakata-Yanagimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shigeru Chiba
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shigeru Chiba .

Editor information

Editors and Affiliations

  1. , EPFL SV ISREC UPRAD, University of Lausanne, Lausanne, 1015, Switzerland

    Freddy Radtke

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Sakata-Yanagimoto, M., Chiba, S. (2012). Notch2 and Immune Function. In: Radtke, F. (eds) Notch Regulation of the Immune System. Current Topics in Microbiology and Immunology, vol 360. Springer, Berlin, Heidelberg. https://doi.org/10.1007/82_2012_235

Download citation

Publish with us

Policies and ethics

Search

Navigation