Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children
Authors: 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. , Del Valle Diane Marie , Kang Gurpawan , Do Anh , Moya Emily , Wilkins Lillian , Le 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 ,   The Mount Sinai COVID-19 Biobank Team, Agashe Charuta , Agrawal Priyal , Alibo Eziwoma , Alvarez Kelvin , Amabile Angelo , Ascolillo Steven , Bailey Rasheed , Begani Priya , Bozkus Cansu Cimen , Bravo Paloma , Brown Stacey-Ann , Buckup Mark , Burka Larissa , Cambron Lena , Carrara Gina , Chang Serena , Chen Steven T. , Chien Jonathan , Chowdhury Mashkura , Cosgrove Dana , Cossarini Francesca , Dave Arpit , Dawson Travis , Dayal Bheesham , Dhainaut Maxime , Dornfeld Rebecca , Dul Katie , Eber Nissan , Fabris Frank , Faith Jeremiah , Falci Dominique , Feng Susie , Fernandes Marie , Geanon Daniel , Grabowska Joanna , Gyimesi Gavin , Hamdani Maha , Handler Diana , Herbinet Manon , Herrera Elva , Hochman Arielle , Hook Jaime , Horta Laila , Humblin Etienne , Johnson Jessica S. , Karim Subha , Kelly Geoffrey , Kim Jong , Lebovitch Dannielle , Lee Brian , Lee Grace , Lee Gyu Ho , Lee Jacky , Leech John , Leventhal Michael B. , Lindblad Katherine , Livanos Alexandra , Machado Rosalie , Mahmood Zafar , Mar Kelcey , Martin Glenn , Maskey Shrisha , Matthews Paul , Meckel Katherine , Mehandru Saurabh , Mercedes Cynthia , Meyer Dara , Mollaoglu Gurkan , Morris Sarah , Nisenholtz Marjorie , Ounadjela Merouane , Patel Vishwendra , Pruitt Cassandra , Rathi Shivani , Redes Jamie , Reyes-Torres Ivan , Rodrigues Alcina , Rodriguez Alfonso , Roudko Vladimir , Ruiz Evelyn , Scalzo Pearl , Schanoski Alessandra Soares , Silva Pedro , Stefanos Hiyab , Straw Meghan , Teague Collin , Upadhyaya Bhaskar , Van Der Heide Verena , Vaninov Natalie , Wacker Daniel , Walsh Hadley , Wilk C. Matthias , Wilson Jessica , Xue Li , Yeboah Naa-akomaah , Young Sabina , Zaks Nina , Zha Renyuan , 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. 
Published: August 2021

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.