The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children.
Adaptive immunity
COVID-19
Immunology
T cells
Tolerance
Journal
The Journal of clinical investigation
ISSN: 1558-8238
Titre abrégé: J Clin Invest
Pays: United States
ID NLM: 7802877
Informations de publication
Date de publication:
03 01 2023
03 01 2023
Historique:
received:
05
07
2022
accepted:
21
10
2022
pubmed:
26
10
2022
medline:
5
1
2023
entrez:
25
10
2022
Statut:
epublish
Résumé
Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.
Identifiants
pubmed: 36282598
pii: 163235
doi: 10.1172/JCI163235
pmc: PMC9797337
doi:
pii:
Substances chimiques
NOTCH1 protein, human
0
Receptor, Notch1
0
CD22 protein, human
0
Sialic Acid Binding Ig-like Lectin 2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK130465
Pays : United States
Organisme : NIAMS NIH HHS
ID : K08 AR073339
Pays : United States
Organisme : NIAMS NIH HHS
ID : P30 AR070253
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI115699
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI065617
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI139633
Pays : United States
Investigateurs
Michele Kong
(M)
Mary Glas Gaspers
(MG)
Katri V. Typpo
(KV)
Ronald C. Sanders Jr.
(RC)
Katherine Irby
(K)
Adam J. Schwarz
(AJ)
Christopher J. Babbitt
(CJ)
Natalie Z. Cvijanovich
(NZ)
Matt S. Zinter
(MS)
Aline B. Maddux
(AB)
Peter M. Mourani
(PM)
Christopher L. Carroll
(CL)
John S. Giuliano Jr.
(JS)
Gwenn E. McLaughlin
(GE)
Keiko M. Tarquinio
(KM)
Kelly N. Michelson
(KN)
Bria M. Coates
(BM)
Courtney M. Rowan
(CM)
Kari Wellnitz
(K)
Guru Bhoojhawon
(G)
Janice E. Sullivan
(JE)
Vicki L. Montgomery
(VL)
Kevin M. Havlin
(KM)
Tamara T. Bradford
(TT)
Becky J. Riggs
(BJ)
Melania M. Bembea
(MM)
Ana Lia Graciano
(AL)
Susan V. Lipton
(SV)
Kimberly L. Marohn
(KL)
Adrienne G. Randolph
(AG)
Margaret M. Newhams
(MM)
Sabrina R. Chen
(SR)
Cameron C. Young
(CC)
Suden Kucukak
(S)
Katherine Kester
(K)
Jane W. Newburger
(JW)
Kevin G. Friedman
(KG)
Mary Beth F. Son
(MBF)
Janet Chou
(J)
Ryan W. Carroll
(RW)
Phoebe H. Yager
(PH)
Neil D. Fernandes
(ND)
Sabrina M. Heidemann
(SM)
Heidi R. Flori
(HR)
Janet R. Hume
(JR)
Emily R. Levy
(ER)
Charlotte V. Hobbs
(CV)
Jennifer E. Schuster
(JE)
Philip C. Spinella
(PC)
Melissa L. Cullimore
(ML)
Russell J. McCulloh
(RJ)
Katharine N. Clouser
(KN)
Rowan F. Walsh
(RF)
Lawrence C. Kleinman
(LC)
Simon Li
(S)
Steven M. Horwitz
(SM)
Shira J. Gertz
(SJ)
Kate G. Ackerman
(KG)
Jill M. Cholette
(JM)
Michael A. Keenaghan
(MA)
Aaolk R. Singh
(AR)
Sheemon P. Zackai
(SP)
Jennifer K. Gillen
(JK)
Adam J. Ratner
(AJ)
Vijaya L. Soma
(VL)
Ilana Harwayne-Gidansky
(I)
Saul R. Hymes
(SR)
Sule Doymaz
(S)
Stephanie P. Schwartz
(SP)
Tracie C. Walker
(TC)
Steven L. Shein
(SL)
Amanda N. Lansell
(AN)
Mark W. Hall
(MW)
Mary A. Staat
(MA)
Julie C. Fitzgerald
(JC)
Jenny L. Bush
(JL)
Ryan H. Burnett
(RH)
Neal J. Thomas
(NJ)
Monica L. Koncicki
(ML)
Ericka L. Fink
(EL)
Joseph A. Carcillo
(JA)
Elizabeth H. Mack
(EH)
Laura Smallcomb
(L)
Natasha B. Halasa
(NB)
Dai Kimura
(D)
Laura L. Loftis
(LL)
Alvaro Coronado Munoz
(A)
Mia Maamari
(M)
Cindy Bowens
(C)
Hillary Crandall
(H)
Lincoln S. Smith
(LS)
John K. McGuire
(JK)
Manish M. Patel
(MM)
Leora R. Feldstein
(LR)
Mark W. Tenforde
(MW)
Ashley M. Jackson
(AM)
Nancy Murray
(N)
Charles E. Rose
(CE)
Commentaires et corrections
Type : CommentIn
Références
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11925-32
pubmed: 8876239
Proc Natl Acad Sci U S A. 2020 Oct 13;117(41):25254-25262
pubmed: 32989130
J Clin Invest. 2013 Apr;123(4):1590-604
pubmed: 23454750
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
PLoS One. 2013 Jul 12;8(7):e68432
pubmed: 23874626
N Engl J Med. 2021 Jul 1;385(1):23-34
pubmed: 34133855
JAMA. 2020 Jul 21;324(3):259-269
pubmed: 32511692
J Clin Invest. 2020 Nov 2;130(11):5967-5975
pubmed: 32730233
Trends Immunol. 2015 Dec;36(12):802-814
pubmed: 26617322
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
N Engl J Med. 2020 Jul 23;383(4):334-346
pubmed: 32598831
Allergy. 2022 Nov;77(11):3377-3387
pubmed: 35841382
J Biol Chem. 2003 Jun 20;278(25):23196-203
pubmed: 12682059
Arthritis Rheumatol. 2020 Jul;72(7):1059-1063
pubmed: 32293098
Nat Immunol. 2020 Nov;21(11):1359-1370
pubmed: 32929274
J Biol Chem. 2000 Jun 9;275(23):17420-7
pubmed: 10748054
Eur J Hum Genet. 2019 Sep;27(9):1398-1405
pubmed: 30979967
Nat Immunol. 2019 Sep;20(9):1208-1219
pubmed: 31384057
JAMA. 2020 May 26;323(20):2052-2059
pubmed: 32320003
Lancet. 2020 Mar 28;395(10229):1054-1062
pubmed: 32171076
Am J Gastroenterol. 2011 Jun;106(6):1147-59
pubmed: 21386831
Pediatrics. 2020 Dec;146(6):
pubmed: 32879033
Nature. 2013 Jul 25;499(7459):485-90
pubmed: 23812589
Cell. 2021 Jun 24;184(13):3573-3587.e29
pubmed: 34062119
Nat Med. 2022 May;28(5):1050-1062
pubmed: 35177862
Front Immunol. 2018 Sep 28;9:2235
pubmed: 30323814
Cell. 2020 Nov 12;183(4):968-981.e7
pubmed: 32966765
Sci Immunol. 2021 May 25;6(59):
pubmed: 34035116
J Allergy Clin Immunol. 2018 Oct;142(4):1243-1256.e17
pubmed: 29627423
Nat Immunol. 2016 Dec;17(12):1459-1466
pubmed: 27695003
J Clin Invest. 2021 Jul 15;131(14):
pubmed: 34032635
Biology (Basel). 2022 Mar 09;11(3):
pubmed: 35336791
J Allergy Clin Immunol. 2021 Sep;148(3):732-738.e1
pubmed: 34224783
Nature. 2021 Mar;591(7848):92-98
pubmed: 33307546
J Clin Invest. 2021 May 17;131(10):
pubmed: 33705359
Front Immunol. 2021 Sep 30;12:741796
pubmed: 34659235
Circulation. 2017 Apr 25;135(17):e927-e999
pubmed: 28356445
Science. 2020 Aug 7;369(6504):706-712
pubmed: 32527925
N Engl J Med. 2020 Dec 17;383(25):2451-2460
pubmed: 32412710
Lancet Rheumatol. 2021 Aug;3(8):e574-e584
pubmed: 34124694
J Leukoc Biol. 2021 Mar;109(3):535-548
pubmed: 32557824
Sci Immunol. 2021 Mar 2;6(57):
pubmed: 33653907
Lancet. 2020 Jun 6;395(10239):1771-1778
pubmed: 32410760
Immunity. 2021 May 11;54(5):1083-1095.e7
pubmed: 33891889
Nat Rev Microbiol. 2021 Mar;19(3):141-154
pubmed: 33024307
Immunity. 2010 Jan 29;32(1):14-27
pubmed: 20152168
Acta Biomed. 2020 Mar 19;91(1):157-160
pubmed: 32191675
Curr Biol. 1997 Apr 1;7(4):261-9
pubmed: 9094314
JAMA Netw Open. 2021 Jun 1;4(6):e2116420
pubmed: 34110391
Nat Genet. 2014 Mar;46(3):310-5
pubmed: 24487276
Immunity. 2021 Jun 8;54(6):1186-1199.e7
pubmed: 33915108
JAMA. 2021 Mar 16;325(11):1074-1087
pubmed: 33625505
N Engl J Med. 2020 Jul 23;383(4):347-358
pubmed: 32598830
Nat Med. 2020 Nov;26(11):1701-1707
pubmed: 32812012
J Biol Chem. 2009 Sep 25;284(39):26427-38
pubmed: 19567869
Nature. 2020 Aug;584(7821):463-469
pubmed: 32717743
Nat Immunol. 2015 Nov;16(11):1162-73
pubmed: 26437242
Cell. 2020 Nov 12;183(4):982-995.e14
pubmed: 32991843
Circulation. 2019 Sep 9;140(10):846-863
pubmed: 31266349
Clin Immunol. 2022 Oct;243:109106
pubmed: 36049601
J Clin Invest. 2021 Oct 15;131(20):
pubmed: 34437303
Nat Immunol. 2016 May;17(5):556-64
pubmed: 26974206
Nature. 2006 May 4;441(7089):101-5
pubmed: 16625202
NPJ Genom Med. 2020 Jul 6;5:29
pubmed: 32655885
J Clin Invest. 2020 Nov 2;130(11):5942-5950
pubmed: 32701511
J Clin Invest. 2021 Mar 15;131(6):
pubmed: 33497356
Nat Commun. 2017 Jan 16;8:14049
pubmed: 28091601
Nat Immunol. 2021 Mar;22(3):381-390
pubmed: 33589816
Nat Med. 2021 Apr;27(4):601-615
pubmed: 33753937
Nat Rev Immunol. 2014 May;14(5):315-28
pubmed: 24762827
J Exp Med. 2022 Feb 7;219(2):
pubmed: 34914824
J Exp Med. 2021 Jun 7;218(6):
pubmed: 33904890