Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children
Noam D. Beckmann, Phillip Comella, Esther Cheng, Lauren Lepow, Aviva G. Beckmann, Scott R. Tyler, Konstantinos Mouskas, Nicole W. Simons, Gabriel E. Hoffman, Nancy Francoeur, Diane M. Del Valle, Gurpawan Kang, Anh Do, Emily Moya, Lillian Wilkins, Jessica Le Bérichel, Christie Chang, Robert Marvin, Sharlene Calorossi, Alona Lansky, Laura Walker, Nancy Yi, Alex W. 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 K. Jaladanki, Charuta Agashe, Ryan C. Thompson, Evan Clark, Bojan Losic, Lauren Peters, The Mount Sinai COVID-19 Biobank Team, Charuta Agashe, Priyal Agrawal, Eziwoma Alibo, Kelvin Alvarez, Angelo Amabile, Steven Ascolillo, Rasheed Bailey, Priya Begani, Cansu Cimen Bozkus, Paloma Bravo, Stacey-Ann Whittaker Brown, Mark Buckup, Larissa Burka, Lena Cambron, Gina Carrara, Serena Chang, Steven T. Chen, Jonathan Chien, Mashkura Chowdhury, Dana Cosgrove, Francesca Cossarini, Arpit Dave, Travis Dawson, Bheesham D. Dayal, Maxime Dhainaut, Rebecca Dornfeld, Katie Dul, Nissan Eber, Frank Fabris, Jeremiah J. Faith, Dominique Falci, Susie Feng, Marie Fernandes, Daniel Geanon
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 CD56 dim CD57 + 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.