The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children

被引：18

作者：

Benamar, Mehdi ^{[1
,2
]}

Chen, Qian ^{[1
,2
]}

Chou, Janet ^{[1
,2
]}

Jule, Amelie M. ^{[1
,2
,3
]}

Boudra, Rafik ^{[4
]}

Contini, Paola ^{[5
,6
]}

Crestani, Elena ^{[1
,2
]}

Lai, Peggy S. ^{[7
,8
]}

Wang, Muyun ^{[1
,2
]}

Fong, Jason ^{[1
,2
]}

Rockwitz, Shira ^{[9
]}

Lee, Pui ^{[1
,2
]}

Chan, Tsz Man Fion ^{[1
,2
]}

Altun, Ekin Zeynep ^{[10
]}

Kepenekli, Eda ^{[11
]}

Karakoc-Aydiner, Elif ^{[12
]}

Ozen, Ahmet ^{[12
]}

Boran, Perran ^{[13
]}

Aygun, Fatih ^{[14
]}

Onal, Pinar ^{[14
]}

Sakalli, Ayse Ayzit Kilinc ^{[14
]}

Cokugras, Haluk ^{[14
]}

Gelmez, Metin Yusuf ^{[15
]}

Oktelik, Fatma Betul ^{[15
]}

Cetin, Esin Aktas ^{[15
]}

Zhong, Yuelin ^{[1
,2
]}

Taylor, Maria Lucia ^{[1
,2
]}

Irby, Katherine ^{[16
]}

Halasa, Natasha B. ^{[17
]}

Mack, Elizabeth H. ^{[18
]}

Signa, Sara ^{[19
,20
]}

Prigione, Ignazia ^{[20
]}

Gattorno, Marco ^{[20
]}

Cotugno, Nicola ^{[21
,22
]}

Amodio, Donato ^{[21
]}

Geha, Raif S. ^{[1
,2
]}

Son, Mary Beth ^{[1
,2
]}

Newburger, Jane ^{[2
,23
]}

Agrawal, Pankaj B. ^{[2
,9
,24
]}

Volpi, Stefano ^{[19
,20
]}

Palma, Paolo ^{[21
,22
]}

Kiykim, Ayca ^{[25
]}

Randolph, Adrienne G. ^{[2
,26
]}

Deniz, Gunnur ^{[15
]}

Baris, Safa ^{[12
]}

De Palma, Raffaele ^{[5
,27
,28
]}

Schmitz-Abe, Klaus ^{[1
,2
,9
]}

Charbonnier, Louis-Marie ^{[1
,2
]}

Henderson, Lauren A. ^{[1
,2
]}

Chatila, Talal A. ^{[1
,2
]}

机构：

[1] Boston Childrens Hosp, Div Immunol, Boston, MA USA

[2] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[3] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[4] Harvard Med Sch, Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA

[5] IRCCS Osped Policlin San Martino, Unit Clin Immunol & Translat Med, Genoa, Italy

[6] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA

[7] Massachusetts Gen Hosp, Div Pulm & Crit Care, Boston, MA 02114 USA

[8] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[9] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA

[10] Marmara Univ Educ & Training Hosp, Dept Pediat, Minist Hlth, Istanbul, Turkiye

[11] Marmara Univ, Div Pediat Infect Dis, Fac Med, Istanbul, Turkiye

[12] Isil Berat Barlan Ctr Translat Med, Div Pediat Allergy & Immunol, Istanbul, Turkiye

[13] Marmara Univ, Div Social Pediat, Fac Med, Istanbul, Turkiye

[14] Istanbul Univ, Div Pediat Allergy & Immunol, Fac Med, Istanbul, Turkiye

[15] Istanbul Univ, Aziz Sancar Inst Expt Med Aziz Sancar DETAE, Dept Immunol, Istanbul, Turkiye

[16] Arkansas Childrens Hosp, 800 Marshall St, Little Rock, AR 72202 USA

[17] Vanderbilt Univ, Med Ctr, Dept Pediat, Div Pediat Infect Dis, Nashville, TN 37232 USA

[18] Med Univ South Carolina, Div Pediat Crit Care Med, Charleston, SC 29425 USA

[19] Univ Genoa, DINOGMI, Genoa, Italy

[20] IRCCS Ist Giannina Gaslini, Ctr Autoinflammatory Dis & Immunodeficiencies, Genoa, Italy

[21] Bambino Gesu Pediat Hosp, IRCCS, Clin & Res Unit Clin Immunol & Vaccinol, Rome, Italy

[22] Univ Roma Tor Vergata, Dept Syst Med, Pediat, Rome, Italy

[23] Boston Childrens Hosp, Dept Cardiol, Boston, MA USA

[24] Harvard Med Sch, Boston Childrens Hosp, Dept Pediat, Div Newborn Med & Genet & Genom, Boston, MA 02115 USA

[25] Istanbul Univ Cerrahpasa, Div Pediat Allergy & Immunol, Fac Med, Istanbul, Turkiye

[26] Boston Childrens Hosp, Dept Anesthesiol Crit Care & Pain Med, Boston, MA USA

[27] Univ Genoa, Dept Internal Med DIMI, Genoa, Italy

[28] CNR Inst Biomol Chem IBC, Naples, Italy

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2023年 / 133卷 / 01期

基金：

新加坡国家研究基金会;

关键词：

KAWASAKI-DISEASE; CELL; RECEPTOR; NOTCH;

D O I：

10.1172/JCI163235

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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 mTORC1dependent 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.

引用

页数：16

共 74 条

[1] Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase B alpha [J].

Alessi, DR ;

James, SR ;

Downes, CP ;

Holmes, AB ;

Gaffney, PRJ ;

Reese, CB ;

Cohen, P .

CURRENT BIOLOGY, 1997, 7 (04) :261-269

[2] Notch in T Cell Differentiation: All Things Considered [J].

Amsen, Derk ;

Helbig, Christina ;

Backer, Ronald A. .

TRENDS IN IMMUNOLOGY, 2015, 36 (12) :802-814

[3] Phosphatase PP2A is requisite for the function of regulatory T cells [J].

Apostolidis, Sokratis A. ;

Rodriguez-Rodriguez, Noe ;

Suarez-Fueyo, Abel ;

Dioufa, Nikolina ;

Ozcan, Esra ;

Crispin, Jose C. ;

Tsokos, Maria G. ;

Tsokos, George C. .

NATURE IMMUNOLOGY, 2016, 17 (05) :556-+

[4] A CD22-Shp1 phosphatase axis controls integrin β7 display and B cell function in mucosal immunity [J].

Ballet, Romain ;

Brennan, Martin ;

Brandl, Carolin ;

Feng, Ningguo ;

Berri, Jeremy ;

Cheng, Julian ;

Ocon, Borja ;

Sheikh, Amin Alborzian Deh ;

Marki, Alex ;

Bi, Yuhan ;

Abram, Clare ;

Lowell, Clifford .

FASEB JOURNAL, 2021, 35

[5] A common IL-4 receptor variant promotes asthma severity via a Treg cell GRB2-IL-6-Notch4 circuit [J].

Benamar, Mehdi ;

Harb, Hani ;

Chen, Qian ;

Wang, Muyun ;

Chan, Tsz Man Fion ;

Fong, Jason ;

Phipatanakul, Wanda ;

Cunningham, Amparito ;

Ertem, Deniz ;

Petty, Carter R. ;

Mousavi, Amirhosein J. ;

Sioutas, Constantinos ;

Crestani, Elena ;

Chatila, Talal A. .

ALLERGY, 2022, 77 (11) :3377-3387

[6] Severe Covid-19 [J].

Berlin, David A. ;

Gulick, Roy M. ;

Martinez, Fernando J. .

NEW ENGLAND JOURNAL OF MEDICINE, 2020, 383 (25) :2451-2460

[7] Type III interferons disrupt the lung epithelial barrier upon viral recognition [J].

Broggi, Achille ;

Ghosh, Sreya ;

Sposito, Benedetta ;

Spreafico, Roberto ;

Balzarini, Fabio ;

Lo Cascio, Antonino ;

Clementi, Nicola ;

De Santis, Maria ;

Mancini, Nicasio ;

Granucci, Francesca ;

Zanoni, Ivan .

SCIENCE, 2020, 369 (6504) :706-+

[8] Peripheral immunophenotypes in children with multisystem inflammatory syndrome associated with SARS-CoV-2 infection [J].

Carter, Michael J. ;

Fish, Matthew ;

Jennings, Aislinn ;

Doores, Katie J. ;

Wellman, Paul ;

Seow, Jeffrey ;

Acors, Sam ;

Graham, Carl ;

Timms, Emma ;

Kenny, Julia ;

Neil, Stuart ;

Malim, Michael H. ;

Tibby, Shane M. ;

Shankar-Hari, Manu .

NATURE MEDICINE, 2020, 26 (11) :1701-+

[9]

Centers for Disease Control and Prevention, EM PREP RESP HAN0043

[10] Functional reprogramming of regulatory T cells in the absence of Foxp3 [J].

Charbonnier, Louis-Marie ;

Cui, Ye ;

Stephen-Victor, Emmanuel ;

Harb, Hani ;

Lopez, David ;

Bleesing, Jack J. ;

Garcia-Lloret, Maria, I ;

Chen, Karin ;

Ozen, Ahmet ;

Carmeliet, Peter ;

Li, Ming O. ;

Pellegrini, Matteo ;

Chatila, Talal A. .

NATURE IMMUNOLOGY, 2019, 20 (09) :1208-+

← 1 2 3 4 5 6 7 8 →