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

Nat Commun. 2021 Aug 11;12(1):4854. doi: 10.1038/s41467-021-24981-1.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • CD56 Antigen / metabolism
  • CD57 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • COVID-19 / genetics
  • COVID-19 / immunology*
  • Child
  • Child, Preschool
  • Down-Regulation
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism
  • Male
  • Mucocutaneous Lymph Node Syndrome / genetics
  • Mucocutaneous Lymph Node Syndrome / immunology
  • SARS-CoV-2 / pathogenicity
  • Systemic Inflammatory Response Syndrome / genetics
  • Systemic Inflammatory Response Syndrome / immunology*
  • Transcriptome / immunology*
  • Young Adult


  • CD56 Antigen
  • CD57 Antigens

Supplementary concepts

  • pediatric multisystem inflammatory disease, COVID-19 related