The deubiquitinase CYLD controls protective immunity against helminth infection by regulation of Treg cell plasticity.
Animals
Cell Plasticity
/ immunology
Deubiquitinating Enzyme CYLD
/ immunology
Helminthiasis
/ immunology
Helminths
/ immunology
Immunity
/ immunology
Inflammation
/ immunology
Interleukin-4
/ immunology
MAP Kinase Kinase Kinases
/ immunology
Mice
Mice, Knockout
NF-kappa B
/ immunology
Nippostrongylus
/ immunology
Signal Transduction
/ immunology
T-Lymphocytes, Regulatory
/ immunology
Th2 Cells
/ immunology
Up-Regulation
/ immunology
CYLD deubiquitinase
Helminth infection
MAPK signaling
NF-κB signaling
Scinderin
Treg cells
lung inflammation
type 2 immunity
Journal
The Journal of allergy and clinical immunology
ISSN: 1097-6825
Titre abrégé: J Allergy Clin Immunol
Pays: United States
ID NLM: 1275002
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
20
04
2020
revised:
22
10
2020
accepted:
28
10
2020
pubmed:
15
12
2020
medline:
13
10
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent. We sought to investigate the role of CYLD in Treg cell function and T Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays. Treg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation. Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into T
Sections du résumé
BACKGROUND
Type 2 immunity can be modulated by regulatory T (Treg) cell activity. It has been suggested that the deubiquitinase cylindromatosis (CYLD) plays a role in the development or function of Treg cells, implying that it could be important for normal protective immunity, where type 2 responses are prevalent.
OBJECTIVE
We sought to investigate the role of CYLD in Treg cell function and T
METHODS
Foxp3-restricted CYLD conditional knockout (KO) mice were examined in mouse models of allergen-induced airway inflammation and Nippostrongylus brasiliensis infection. We performed multiplex magnetic bead assays, flow cytometry, and quantitative PCR to understand how a lack of CYLD affected cytokine production, homing, and suppression in Treg cells. Target genes regulated by CYLD were identified and validated by microarray analysis, coimmunoprecipitation, short hairpin RNA knockdown, and transfection assays.
RESULTS
Treg cell-specific CYLD KO mice showed severe spontaneous pulmonary inflammation with increased migration of Treg cells into the lung. CYLD-deficient Treg cells furthermore produced high levels of IL-4 and failed to suppress allergen-induced lung inflammation. Supporting this, the conditional KO mice displayed enhanced protection against N brasiliensis infection by contributing to type 2 immunity. Treg cell conversion into IL-4-producing cells was due to augmented mitogen-activated protein kinase and nuclear factor κB signaling. Moreover, Scinderin, a member of the actin-binding gelsolin family, was highly upregulated in CYLD-deficient Treg cells, and controlled IL-4 production through forming complexes with mitogen-activated protein kinase kinase/extracellular receptor kinase. Correspondingly, both excessive IL-4 production in vivo and the protective role of CYLD-deficient Treg cells against N brasiliensis were reversed by Scinderin ablation.
CONCLUSIONS
Our findings indicate that CYLD controls type 2 immune responses by regulating Treg cell conversion into T
Identifiants
pubmed: 33309741
pii: S0091-6749(20)31706-1
doi: 10.1016/j.jaci.2020.10.042
pmc: PMC8729234
mid: NIHMS1653845
pii:
doi:
Substances chimiques
NF-kappa B
0
Interleukin-4
207137-56-2
MAP Kinase Kinase Kinases
EC 2.7.11.25
CYLD protein, mouse
EC 3.4.19.12
Deubiquitinating Enzyme CYLD
EC 3.4.19.12
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
209-224.e9Subventions
Organisme : NIAID NIH HHS
ID : R01 AI140130
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI122258
Pays : United States
Informations de copyright
Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Références
Immunity. 2008 Apr;28(4):546-58
pubmed: 18387831
Nat Immunol. 2009 Sep;10(9):1000-7
pubmed: 19633673
Immunity. 2014 Aug 21;41(2):283-95
pubmed: 25088770
Am J Physiol Lung Cell Mol Physiol. 2009 Feb;296(2):L185-97
pubmed: 19028979
Immunity. 2009 May;30(5):636-45
pubmed: 19464986
Immunity. 2018 Jun 19;48(6):1195-1207.e6
pubmed: 29907525
Crit Rev Immunol. 2012;32(1):65-79
pubmed: 22428855
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19396-401
pubmed: 19036923
J Exp Med. 2011 Aug 29;208(9):1863-74
pubmed: 21825018
J Immunol. 2013 Oct 1;191(7):3694-704
pubmed: 23986534
Immunity. 2015 Jul 21;43(1):161-74
pubmed: 26092469
Cytokine. 2002 Jun 21;18(6):295-303
pubmed: 12160517
Nat Genet. 2001 Jan;27(1):20-1
pubmed: 11137993
Immunity. 2015 Mar 17;42(3):512-23
pubmed: 25769611
J Biol Chem. 2011 Nov 25;286(47):40520-30
pubmed: 21931165
Nature. 2010 Feb 18;463(7283):963-7
pubmed: 20164930
Immunity. 2001 Mar;14(3):315-29
pubmed: 11290340
J Immunol. 2012 Nov 15;189(10):4770-6
pubmed: 23066153
Med Res Rev. 2012 Sep;32(5):999-1025
pubmed: 22886630
Cell Rep. 2017 Jul 18;20(3):757-770
pubmed: 28723576
Immunity. 2013 Oct 17;39(4):733-43
pubmed: 24076051
Mol Cell Biol. 1998 Aug;18(8):4589-96
pubmed: 9671468
Nat Immunol. 2005 Apr;6(4):345-52
pubmed: 15785760
Nature. 2003 Aug 14;424(6950):801-5
pubmed: 12917691
Nat Genet. 2000 Jun;25(2):160-5
pubmed: 10835629
J Allergy Clin Immunol. 2007 May;119(5):1258-66
pubmed: 17412402
J Immunol. 2010 May 1;184(9):4688-95
pubmed: 20304823
Eur J Immunol. 2007 Jul;37(7):1874-86
pubmed: 17563918
J Allergy Clin Immunol. 2016 Sep;138(3):666-675
pubmed: 27476889
Dev Biol. 2007 Feb 15;302(2):427-37
pubmed: 17097081
PLoS One. 2012;7(10):e43035
pubmed: 23071489
J Exp Med. 2017 Jun 5;214(6):1809-1826
pubmed: 28507062
Immunity. 2016 Nov 15;45(5):1122-1134
pubmed: 27851913
Blood. 2009 Jun 4;113(23):5891-5
pubmed: 19342479
Nature. 2003 Aug 14;424(6950):793-6
pubmed: 12917689
J Exp Med. 1999 May 17;189(10):1565-72
pubmed: 10330435
Curr Opin Immunol. 2003 Dec;15(6):690-6
pubmed: 14630204
Science. 2010 Sep 24;329(5999):1667-71
pubmed: 20929851
J Clin Invest. 2013 Dec;123(12):5165-78
pubmed: 24270422
Gut. 2014 Aug;63(8):1265-74
pubmed: 24092863
J Clin Invest. 2013 Nov;123(11):4923-34
pubmed: 24135136
Nat Immunol. 2016 Mar;17(3):286-96
pubmed: 26829767
Nat Genet. 2001 Jan;27(1):18-20
pubmed: 11137992
J Immunol. 2012 Nov 15;189(10):4759-69
pubmed: 23053511
FASEB J. 2015 Jun;29(6):2281-91
pubmed: 25681458
Annu Rev Immunol. 2017 Apr 26;35:53-84
pubmed: 27912316
Int J Parasitol. 2007 Oct;37(12):1367-78
pubmed: 17555758
Cell Death Differ. 2010 Jan;17(1):25-34
pubmed: 19373246
J Exp Med. 2007 Jun 11;204(6):1475-85
pubmed: 17548520
Cell. 1997 May 16;89(4):587-96
pubmed: 9160750
Nature. 2015 Aug 27;524(7566):476-80
pubmed: 26287461
J Exp Med. 2007 Oct 29;204(11):2615-27
pubmed: 17923499
J Immunol. 2016 May 15;196(10):3975-82
pubmed: 27183634
Nat Commun. 2017 Nov 23;8(1):1741
pubmed: 29170498
Exp Mol Med. 2015 Dec 18;47:e199
pubmed: 26642432
J Cell Sci. 2010 Jan 15;123(Pt 2):171-80
pubmed: 20026643
J Allergy Clin Immunol. 2009 Jan;123(1):67-73.e3
pubmed: 19062085
Cell Rep. 2016 Jun 14;15(11):2449-61
pubmed: 27264187
J Immunol. 2011 Apr 1;186(7):4295-305
pubmed: 21335490
Immunity. 2015 Jun 16;42(6):1062-74
pubmed: 26084024
Nat Immunol. 2014 Feb;15(2):186-94
pubmed: 24317039
J Immunol. 2008 Nov 1;181(9):6456-66
pubmed: 18941236
Curr Opin Cell Biol. 1999 Feb;11(1):103-8
pubmed: 10047530