Notch Signaling Regulates Mouse and Human Th17 Differentiation

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2011 Jun 21

PMID 21685328

Citations 76

Authors

Shilpa Keerthivasan

Reem Suleiman

Rebecca Lawlor

Justine Roderick

Tonya Bates

Lisa Minter

Juan Anguita

Ignacio Juncadella

Brian J Nickoloff

I Caroline Le Poole

Lucio Miele

Barbara A Osborne

Affiliations

Soon will be listed here.

Abstract

Th17 cells are known to play a critical role in adaptive immune responses to several important extracellular pathogens. Additionally, Th17 cells are implicated in the pathogenesis of several autoimmune and inflammatory disorders as well as in cancer. Therefore, it is essential to understand the mechanisms that regulate Th17 differentiation. Notch signaling is known to be important at several stages of T cell development and differentiation. In this study, we report that Notch1 is activated in both mouse and human in vitro-polarized Th17 cells and that blockade of Notch signaling significantly downregulates the production of Th17-associated cytokines, suggesting an intrinsic requirement for Notch during Th17 differentiation in both species. We also present evidence, using promoter reporter assays, knockdown studies, as well as chromatin immunoprecipitation, that IL-17 and retinoic acid-related orphan receptor γt are direct transcriptional targets of Notch signaling in Th17 cells. Finally, in vivo inhibition of Notch signaling reduced IL-17 production and Th17-mediated disease progression in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Thus, this study highlights the importance of Notch signaling in Th17 differentiation and indicates that selective targeted therapy against Notch may be an important tool to treat autoimmune disorders, including multiple sclerosis.

Citing Articles

Astrocytic DLL4-NOTCH1 signaling pathway promotes neuroinflammation via the IL-6-STAT3 axis.

Mora P, Laisne M, Bourguignon C, Rouault P, Jaspard-Vinassa B, Maitre M J Neuroinflammation. 2024; 21(1):258.

PMID: 39390606 PMC: 11468415. DOI: 10.1186/s12974-024-03246-w.

The histone methyltransferase Mixed-lineage-leukemia-1 drives T cell phenotype via Notch signaling in diabetic tissue repair.

Melvin W, Bauer T, Mangum K, Audu C, Shadiow J, Barrett E JCI Insight. 2024; 9(19).

PMID: 39250432 PMC: 11463913. DOI: 10.1172/jci.insight.179012.

Altered memory CCR6 Th17-polarised T-cell function and biology in people with HIV under successful antiretroviral therapy and HIV elite controllers.

Yero A, Goulet J, Shi T, Costiniuk C, Routy J, Tremblay C EBioMedicine. 2024; 107:105274.

PMID: 39178742 PMC: 11388266. DOI: 10.1016/j.ebiom.2024.105274.

Notch Signaling in Central Nervous System: From Cellular Development to Multiple Sclerosis Disease.

Askari H, Rabiei F, Yahyazadeh M, Biagini G, Ghasemi-Kasman M Curr Neuropharmacol. 2024; 23(1):3-19.

PMID: 39162293 PMC: 11519821. DOI: 10.2174/1570159X22666240731114906.

is positively correlated with in infection and a biomarker for mucosal injury.

Jinling X, Guoan L, Chuxi C, Qiaoyuan L, Yinzhong C, Shihao C iScience. 2024; 27(7):110323.

PMID: 39055908 PMC: 11269956. DOI: 10.1016/j.isci.2024.110323.

References

Bettelli E, Carrier Y, Gao W, Korn T, Strom T, Oukka M . Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006; 441(7090):235-8. DOI: 10.1038/nature04753. View

Matusevicius D, Kivisakk P, He B, Kostulas N, Ozenci V, Fredrikson S . Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler. 1999; 5(2):101-4. DOI: 10.1177/135245859900500206. View

Liotta F, Frosali F, Querci V, Mantei A, Fili L, Maggi L . Human immature myeloid dendritic cells trigger a TH2-polarizing program via Jagged-1/Notch interaction. J Allergy Clin Immunol. 2008; 121(4):1000-5.e8. DOI: 10.1016/j.jaci.2008.01.004. View

Quintana F, Basso A, Iglesias A, Korn T, Farez M, Bettelli E . Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008; 453(7191):65-71. DOI: 10.1038/nature06880. View

Serada S, Fujimoto M, Mihara M, Koike N, Ohsugi Y, Nomura S . IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2008; 105(26):9041-6. PMC: 2449361. DOI: 10.1073/pnas.0802218105. View

Shin H, Minter L, Cho O, Gottipati S, Fauq A, Golde T . Notch1 augments NF-kappaB activity by facilitating its nuclear retention. EMBO J. 2005; 25(1):129-38. PMC: 1356346. DOI: 10.1038/sj.emboj.7600902. View

Ziegler S, Buckner J . FOXP3 and the regulation of Treg/Th17 differentiation. Microbes Infect. 2009; 11(5):594-8. PMC: 2728495. DOI: 10.1016/j.micinf.2009.04.002. View

Minter L, Turley D, Das P, Shin H, Joshi I, Lawlor R . Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21. Nat Immunol. 2005; 6(7):680-8. View

Bettelli E, Korn T, Kuchroo V . Th17: the third member of the effector T cell trilogy. Curr Opin Immunol. 2007; 19(6):652-7. PMC: 2288775. DOI: 10.1016/j.coi.2007.07.020. View

10.

Deftos M, Bevan M . Notch signaling in T cell development. Curr Opin Immunol. 2000; 12(2):166-72. DOI: 10.1016/s0952-7915(99)00067-9. View

11.

Peters M, Dudziak K, Stiehm M, Bufe A . T-cell polarization depends on concentration of the danger signal used to activate dendritic cells. Immunol Cell Biol. 2010; 88(5):537-44. DOI: 10.1038/icb.2010.3. View

12.

Osborne B, Minter L . Notch signalling during peripheral T-cell activation and differentiation. Nat Rev Immunol. 2006; 7(1):64-75. DOI: 10.1038/nri1998. View

13.

Mukherjee S, Schaller M, Neupane R, Kunkel S, Lukacs N . Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation. J Immunol. 2009; 182(12):7381-8. PMC: 2980695. DOI: 10.4049/jimmunol.0804322. View

14.

Perumalsamy L, Nagala M, Sarin A . Notch-activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival. Proc Natl Acad Sci U S A. 2010; 107(15):6882-7. PMC: 2872423. DOI: 10.1073/pnas.0910060107. View

15.

Skokos D, Nussenzweig M . CD8- DCs induce IL-12-independent Th1 differentiation through Delta 4 Notch-like ligand in response to bacterial LPS. J Exp Med. 2007; 204(7):1525-31. PMC: 2118646. DOI: 10.1084/jem.20062305. View

16.

Perumalsamy L, Nagala M, Banerjee P, Sarin A . A hierarchical cascade activated by non-canonical Notch signaling and the mTOR-Rictor complex regulates neglect-induced death in mammalian cells. Cell Death Differ. 2009; 16(6):879-89. DOI: 10.1038/cdd.2009.20. View

17.

Zhou L, Littman D . Transcriptional regulatory networks in Th17 cell differentiation. Curr Opin Immunol. 2009; 21(2):146-52. PMC: 2701391. DOI: 10.1016/j.coi.2009.03.001. View

18.

Liu X, Lin X, Gaffen S . Crucial role for nuclear factor of activated T cells in T cell receptor-mediated regulation of human interleukin-17. J Biol Chem. 2004; 279(50):52762-71. DOI: 10.1074/jbc.M405764200. View

19.

Shamsul Alam M, Maekawa Y, Kitamura A, Tanigaki K, Yoshimoto T, Kishihara K . Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A. 2010; 107(13):5943-8. PMC: 2851859. DOI: 10.1073/pnas.0911755107. View

20.

Radtke F, Wilson A, MacDonald H . Notch signaling in T- and B-cell development. Curr Opin Immunol. 2004; 16(2):174-9. DOI: 10.1016/j.coi.2004.01.002. View