Notch2 Receptor Signaling Controls Functional Differentiation of Dendritic Cells in the Spleen and Intestine

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2011 Oct 25

PMID 22018469

Citations 262

Authors

Kanako L Lewis

Michele L Caton

Milena Bogunovic

Melanie Greter

Lucja T Grajkowska

Dennis Ng

Apostolos Klinakis

Israel F Charo

Steffen Jung

Jennifer L Gommerman

Ivaylo I Ivanov

Kang Liu

Miriam Merad

Boris Reizis

Affiliations

Soon will be listed here.

Abstract

Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b(+) DC subset, Notch signaling blockade ablated a distinct population marked by high expression of the adhesion molecule Esam. The Notch-dependent Esam(hi) DC subset required lymphotoxin beta receptor signaling, proliferated in situ, and facilitated CD4(+) T cell priming. The Notch-independent Esam(lo) DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b(+)CD103(+) DCs in the intestinal lamina propria and to a corresponding decrease of IL-17-producing CD4(+) T cells in the intestine. Thus, Notch2 is a common differentiation signal for T cell-priming CD11b(+) DC subsets in the spleen and intestine.

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References

Yuan J, Kousis P, Suliman S, Visan I, Guidos C . Functions of notch signaling in the immune system: consensus and controversies. Annu Rev Immunol. 2010; 28:343-65. DOI: 10.1146/annurev.immunol.021908.132719. View

Radtke F, Ferrero I, Wilson A, Lees R, Aguet M, MacDonald H . Notch1 deficiency dissociates the intrathymic development of dendritic cells and T cells. J Exp Med. 2000; 191(7):1085-94. PMC: 2193172. DOI: 10.1084/jem.191.7.1085. View

Maillard I, Weng A, Carpenter A, Rodriguez C, Sai H, Xu L . Mastermind critically regulates Notch-mediated lymphoid cell fate decisions. Blood. 2004; 104(6):1696-702. DOI: 10.1182/blood-2004-02-0514. View

Feng F, Wang Y, Hu X, Liu X, Ji G, Chen Y . The transcription factor RBP-J-mediated signaling is essential for dendritic cells to evoke efficient anti-tumor immune responses in mice. Mol Cancer. 2010; 9:90. PMC: 2867822. DOI: 10.1186/1476-4598-9-90. View

Bogunovic M, Ginhoux F, Helft J, Shang L, Hashimoto D, Greter M . Origin of the lamina propria dendritic cell network. Immunity. 2009; 31(3):513-25. PMC: 2778256. DOI: 10.1016/j.immuni.2009.08.010. View

Hozumi K, Negishi N, Suzuki D, Abe N, Sotomaru Y, Tamaoki N . Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat Immunol. 2004; 5(6):638-44. DOI: 10.1038/ni1075. View

Yashiro-Ohtani Y, Ohtani T, Pear W . Notch regulation of early thymocyte development. Semin Immunol. 2010; 22(5):261-9. DOI: 10.1016/j.smim.2010.04.015. View

Saederup N, Cardona A, Croft K, Mizutani M, Cotleur A, Tsou C . Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One. 2010; 5(10):e13693. PMC: 2965160. DOI: 10.1371/journal.pone.0013693. View

Sharov A, Dudekula D, Ko M . A web-based tool for principal component and significance analysis of microarray data. Bioinformatics. 2005; 21(10):2548-9. DOI: 10.1093/bioinformatics/bti343. View

10.

Zhou J, Cheng P, Youn J, Cotter M, Gabrilovich D . Notch and wingless signaling cooperate in regulation of dendritic cell differentiation. Immunity. 2009; 30(6):845-59. PMC: 2700307. DOI: 10.1016/j.immuni.2009.03.021. View

11.

Pellegrinet L, Rodilla V, Liu Z, Chen S, Koch U, Espinosa L . Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. Gastroenterology. 2011; 140(4):1230-1240.e1-7. PMC: 3066401. DOI: 10.1053/j.gastro.2011.01.005. View

12.

Cheng P, Nefedova Y, Miele L, Osborne B, Gabrilovich D . Notch signaling is necessary but not sufficient for differentiation of dendritic cells. Blood. 2003; 102(12):3980-8. DOI: 10.1182/blood-2003-04-1034. View

13.

Steinman R, Idoyaga J . Features of the dendritic cell lineage. Immunol Rev. 2010; 234(1):5-17. DOI: 10.1111/j.0105-2896.2009.00888.x. View

14.

Denning T, Norris B, Medina-Contreras O, Manicassamy S, Geem D, Madan R . 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. 2011; 187(2):733-47. PMC: 3131424. DOI: 10.4049/jimmunol.1002701. View

15.

Tu L, Fang T, Artis D, Shestova O, Pross S, Maillard I . Notch signaling is an important regulator of type 2 immunity. J Exp Med. 2005; 202(8):1037-42. PMC: 2213210. DOI: 10.1084/jem.20050923. View

16.

Naik S, Metcalf D, Van Nieuwenhuijze A, Wicks I, Wu L, OKeeffe M . Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes. Nat Immunol. 2006; 7(6):663-71. DOI: 10.1038/ni1340. View

17.

Barnden M, Allison J, Heath W, Carbone F . Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol Cell Biol. 1998; 76(1):34-40. DOI: 10.1046/j.1440-1711.1998.00709.x. View

18.

Lahoud M, Proietto A, Ahmet F, Kitsoulis S, Eidsmo L, Wu L . The C-type lectin Clec12A present on mouse and human dendritic cells can serve as a target for antigen delivery and enhancement of antibody responses. J Immunol. 2009; 182(12):7587-94. DOI: 10.4049/jimmunol.0900464. View

19.

McCright B, Lozier J, Gridley T . Generation of new Notch2 mutant alleles. Genesis. 2006; 44(1):29-33. DOI: 10.1002/gene.20181. View

20.

Dudziak D, Kamphorst A, Heidkamp G, Buchholz V, Trumpfheller C, Yamazaki S . Differential antigen processing by dendritic cell subsets in vivo. Science. 2007; 315(5808):107-11. DOI: 10.1126/science.1136080. View