Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children

Beckmann, Noam D.; Comella, Phillip H.; Cheng, Esther; Lepow, Lauren; Beckmann, Aviva G.; Mouskas, Konstantinos; Simons, Nicole W.; Hoffman, Gabriel E.; Francoeur, Nancy J.; Del Valle, Diane Marie; Kang, Gurpawan; Moya, Emily; Wilkins, Lillian; Le Berichel, Jessica; Chang, Christie; Marvin, Robert; Calorossi, Sharlene; Lansky, Alona; Walker, Laura; Yi, Nancy; Yu, Alex; Hartnett, Matthew; Eaton, Melody; Hatem, Sandra; Jamal, Hajra; Akyatan, Alara; Tabachnikova, Alexandra; Liharska, Lora E.; Cotter, Liam; Fennessey, Brian; Vaid, Akhil; Barturen, Guillermo; Tyler, Scott R.; 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; Argueta, Kimberly; Harris, Jocelyn; Karekar, Neha; Batchelor, Craig; Lacunza, Jose; Yishak, Mahlet; Tuballes, Kevin; Scott, Leisha; Kumar, Arvind; Jaladanki, Suraj; Thompson, Ryan; Clark, Evan; Losic, Bojan; 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; 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.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8(+) T-cells and CD56(dim)CD57(+) NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21, a central coordinator of exhausted CD8(+) T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.