Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children

Beckmann, Noam D.; Comella, Phillip H.; Cheng, Esther; Lepow, Lauren; Beckmann, Aviva G.; Tyler, Scott R.; Mouskas, Konstantinos; Simons, Nicole W.; Hoffman, Gabriel E.; Francoeur, Nancy J.; Valle, Diane Marie; Kang, Gurpawan; Do, Anh; Moya, Emily; Wilkins, Lillian; Berichel, Jessica; Chang, Christie; Marvin, Robert; Calorossi, Sharlene; Lansky, Alona; Walker, Laura; Yi, Nancy; Yu, Alex; Chung, Jonathan; Hartnett, Matthew; Eaton, Melody; Hatem, Sandra; Jamal, Hajra; Akyatan, Alara; Tabachnikova, Alexandra; Liharska, Lora E.; Cotter, Liam; Fennessy, Brian; Vaid, Akhil; Barturen, Guillermo; Shah, Hardik; Wang, Ying-chih; Sridhar, Shwetha Hara; Soto, Juan; Bose, Swaroop; Madrid, Kent; Ellis, Ethan; Merzier, Elyze; Vlachos, Konstantinos; Fishman, Nataly; Tin, Manying; Smith, Melissa; Xie, Hui; Patel, Manishkumar; Nie, Kai; Argueta, Kimberly; Harris, Jocelyn; Karekar, Neha; Batchelor, Craig; Lacunza, Jose; Yishak, Mahlet; Tuballes, Kevin; Scott, Ieisha; Kumar, Arvind; Jaladanki, Suraj; Agashe, Charuta; Thompson, Ryan; Clark, Evan; Losic, Bojan; Peters, Lauren; Roussos, Panagiotis; Zhu, Jun; Wang, Wenhui; Kasarskis, Andrew; Glicksberg, Benjamin S.; Nadkarni, Girish; Bogunovic, Dusan; Elaiho, Cordelia; Gangadharan, Sandeep; Ofori-Amanfo, George; Alesso-Carra, Kasey; Onel, Kenan; Wilson, Karen M.; Argmann, Carmen; Bunyavanich, Supinda; Alarcón-Riquelme, Marta E.; Marron, Thomas U.; Rahman, Adeeb; Kim-Schulze, Seunghee; Gnjatic, Sacha; Gelb, Bruce D.; Merad, Miriam; Sebra, Robert; Schadt, Eric E.; Charney, Alexander W.

Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children

Noam D. Beckmann (), Phillip H. Comella, Esther Cheng, Lauren Lepow, Aviva G. Beckmann, Scott R. Tyler, Konstantinos Mouskas, Nicole W. Simons, Gabriel E. Hoffman, Nancy J. Francoeur, Diane Marie Valle, Gurpawan Kang, Anh Do, Emily Moya, Lillian Wilkins, Jessica Berichel, Christie Chang, Robert Marvin, Sharlene Calorossi, Alona Lansky, Laura Walker, Nancy Yi, Alex Yu, Jonathan Chung, Matthew Hartnett, Melody Eaton, Sandra Hatem, Hajra Jamal, Alara Akyatan, Alexandra Tabachnikova, Lora E. Liharska, Liam Cotter, Brian Fennessy, Akhil Vaid, Guillermo Barturen, Hardik Shah, Ying-chih Wang, Shwetha Hara Sridhar, Juan Soto, Swaroop Bose, Kent Madrid, Ethan Ellis, Elyze Merzier, Konstantinos Vlachos, Nataly Fishman, Manying Tin, Melissa Smith, Hui Xie, Manishkumar Patel, Kai Nie, Kimberly Argueta, Jocelyn Harris, Neha Karekar, Craig Batchelor, Jose Lacunza, Mahlet Yishak, Kevin Tuballes, Ieisha Scott, Arvind Kumar, Suraj Jaladanki, Charuta Agashe, Ryan Thompson, Evan Clark, Bojan Losic, Lauren Peters, Panagiotis Roussos, Jun Zhu, Wenhui Wang, Andrew Kasarskis, Benjamin S. Glicksberg, Girish Nadkarni, Dusan Bogunovic, Cordelia Elaiho, Sandeep Gangadharan, George Ofori-Amanfo, Kasey Alesso-Carra, Kenan Onel, Karen M. Wilson, Carmen Argmann, Supinda Bunyavanich, Marta E. Alarcón-Riquelme, Thomas U. Marron, Adeeb Rahman, Seunghee Kim-Schulze, Sacha Gnjatic, Bruce D. Gelb, Miriam Merad, Robert Sebra, Eric E. Schadt () and Alexander W. Charney ()
Additional contact information
Noam D. Beckmann: Icahn School of Medicine at Mount Sinai
Phillip H. Comella: Icahn School of Medicine at Mount Sinai
Esther Cheng: Icahn School of Medicine at Mount Sinai
Lauren Lepow: Icahn School of Medicine at Mount Sinai
Aviva G. Beckmann: Icahn School of Medicine at Mount Sinai
Scott R. Tyler: Icahn School of Medicine at Mount Sinai
Konstantinos Mouskas: Icahn School of Medicine at Mount Sinai
Nicole W. Simons: Icahn School of Medicine at Mount Sinai
Gabriel E. Hoffman: Icahn School of Medicine at Mount Sinai
Nancy J. Francoeur: Icahn School of Medicine at Mount Sinai
Diane Marie Valle: Icahn School of Medicine at Mount Sinai
Gurpawan Kang: Icahn School of Medicine at Mount Sinai
Anh Do: Icahn School of Medicine at Mount Sinai
Emily Moya: Icahn School of Medicine at Mount Sinai
Lillian Wilkins: Icahn School of Medicine at Mount Sinai
Jessica Berichel: Icahn School of Medicine at Mount Sinai
Christie Chang: Icahn School of Medicine at Mount Sinai
Robert Marvin: Icahn School of Medicine at Mount Sinai
Sharlene Calorossi: Icahn School of Medicine at Mount Sinai
Alona Lansky: Icahn School of Medicine at Mount Sinai
Laura Walker: Icahn School of Medicine at Mount Sinai
Nancy Yi: Icahn School of Medicine at Mount Sinai
Alex Yu: Icahn School of Medicine at Mount Sinai
Jonathan Chung: Icahn School of Medicine at Mount Sinai
Matthew Hartnett: Icahn School of Medicine at Mount Sinai
Melody Eaton: Icahn School of Medicine at Mount Sinai
Sandra Hatem: Icahn School of Medicine at Mount Sinai
Hajra Jamal: Icahn School of Medicine at Mount Sinai
Alara Akyatan: Icahn School of Medicine at Mount Sinai
Alexandra Tabachnikova: Icahn School of Medicine at Mount Sinai
Lora E. Liharska: Icahn School of Medicine at Mount Sinai
Liam Cotter: Icahn School of Medicine at Mount Sinai
Brian Fennessy: Icahn School of Medicine at Mount Sinai
Akhil Vaid: Icahn School of Medicine at Mount Sinai
Guillermo Barturen: Center for Genomics and Oncological Research Pfizer/University of Granada/Andalusian Regional Government (GENYO)
Hardik Shah: Icahn School of Medicine at Mount Sinai
Ying-chih Wang: Icahn School of Medicine at Mount Sinai
Shwetha Hara Sridhar: Icahn School of Medicine at Mount Sinai
Juan Soto: Icahn School of Medicine at Mount Sinai
Swaroop Bose: Icahn School of Medicine at Mount Sinai
Kent Madrid: Icahn School of Medicine at Mount Sinai
Ethan Ellis: Icahn School of Medicine at Mount Sinai
Elyze Merzier: Icahn School of Medicine at Mount Sinai
Konstantinos Vlachos: Icahn School of Medicine at Mount Sinai
Nataly Fishman: Icahn School of Medicine at Mount Sinai
Manying Tin: Icahn School of Medicine at Mount Sinai
Melissa Smith: Icahn School of Medicine at Mount Sinai
Hui Xie: Icahn School of Medicine at Mount Sinai
Manishkumar Patel: Icahn School of Medicine at Mount Sinai
Kai Nie: Icahn School of Medicine at Mount Sinai
Kimberly Argueta: Icahn School of Medicine at Mount Sinai
Jocelyn Harris: Icahn School of Medicine at Mount Sinai
Neha Karekar: Icahn School of Medicine at Mount Sinai
Craig Batchelor: Icahn School of Medicine at Mount Sinai
Jose Lacunza: Icahn School of Medicine at Mount Sinai
Mahlet Yishak: Icahn School of Medicine at Mount Sinai
Kevin Tuballes: Icahn School of Medicine at Mount Sinai
Ieisha Scott: Icahn School of Medicine at Mount Sinai
Arvind Kumar: Icahn School of Medicine at Mount Sinai
Suraj Jaladanki: Icahn School of Medicine at Mount Sinai
Charuta Agashe: Icahn School of Medicine at Mount Sinai
Ryan Thompson: Icahn School of Medicine at Mount Sinai
Evan Clark: Icahn School of Medicine at Mount Sinai
Bojan Losic: Icahn School of Medicine at Mount Sinai
Lauren Peters: Icahn School of Medicine at Mount Sinai
Panagiotis Roussos: Icahn School of Medicine at Mount Sinai
Jun Zhu: Icahn School of Medicine at Mount Sinai
Wenhui Wang: Icahn School of Medicine at Mount Sinai
Andrew Kasarskis: Icahn School of Medicine at Mount Sinai
Benjamin S. Glicksberg: Icahn School of Medicine at Mount Sinai
Girish Nadkarni: Mount Sinai COVID Informatics Center
Dusan Bogunovic: Icahn School of Medicine at Mount Sinai
Cordelia Elaiho: Icahn School of Medicine at Mount Sinai
Sandeep Gangadharan: Icahn School of Medicine at Mount Sinai
George Ofori-Amanfo: Icahn School of Medicine at Mount Sinai
Kasey Alesso-Carra: Icahn School of Medicine at Mount Sinai
Kenan Onel: Icahn School of Medicine at Mount Sinai
Karen M. Wilson: Icahn School of Medicine at Mount Sinai
Carmen Argmann: Icahn School of Medicine at Mount Sinai
Supinda Bunyavanich: Icahn School of Medicine at Mount Sinai
Marta E. Alarcón-Riquelme: Icahn School of Medicine at Mount Sinai
Thomas U. Marron: Icahn School of Medicine at Mount Sinai
Adeeb Rahman: Icahn School of Medicine at Mount Sinai
Seunghee Kim-Schulze: Icahn School of Medicine at Mount Sinai
Sacha Gnjatic: Icahn School of Medicine at Mount Sinai
Bruce D. Gelb: Icahn School of Medicine at Mount Sinai
Miriam Merad: Icahn School of Medicine at Mount Sinai
Robert Sebra: Icahn School of Medicine at Mount Sinai
Eric E. Schadt: Icahn School of Medicine at Mount Sinai
Alexander W. Charney: Icahn School of Medicine at Mount Sinai

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.

Date: 2021
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DOI: 10.1038/s41467-021-24981-1

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