With the delta variant on the rise, and children under 12 unable to receive the vaccine, it is critical to gain a deeper understanding of multisystem inflammatory syndrome in children (MIS-C)—the rare but serious complication that occurs in some children weeks after an infection with SARS-CoV-2. MIS-C presents with fever, inflammation, and pathology of multiple organs. Now, researchers have uncovered that two types of immune cells, natural killer (NK) cells and CD8+ T cells, are downregulated in children with MIS-C, and that this is associated with a sustained inflammatory response, a hallmark of infection with SARS-CoV-2.

This research is published today in Nature Communications in the paper, “Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

“Our study implicated T-cell exhaustion in MIS-C patients as one of the potential drivers of this disease, suggesting that an increase in both NK cells and circulating exhausted CD8+ T cells may improve inflammatory disease symptoms,” said lead co-author Noam Beckmann, PhD, assistant professor of genetics and genomic sciences, and member of the Mount Sinai Clinical Intelligence Center (MSCIC), at the Icahn School of Medicine at Mount Sinai. “Additionally, we found nine key regulators of this network known to have associations with NK cell and exhausted CD8+ T cell functionality.”

MIS-C is characterized by fever, pain, and inflammation of multiple organs including the heart, lungs, kidneys, skin, eyes, or gastrointestinal tract. More than 2,600 cases of MIS-C have been reported in the United States since the COVID-19 pandemic began. While an autoimmune condition has been suggested as an underlying cause, specific genes, pathways, and cell types remain unknown.

The team performed 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, the authors wrote, is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named.

Through the Mount Sinai team’s gene-expression study, the researchers have taken a significant step in providing the field with new exploratory pathways involving complex networks and subnetworks of genes they constructed from pediatric cases of MIS-C and COVID-19 from the Mount Sinai COVID-19 Biobank.

One of the more significant of these gene networks implicated the suppression of two types of immune cells: NK cells and CD8+ T cells. Previous research has shown that when CD8+ T cells are persistently exposed to pathogens, they enter a state of “exhaustion,” resulting in a loss of their effectiveness and ability to proliferate. The researchers in the new study specifically pointed to the CD8+ T cells being in this exhausted state, thus potentially weakening the inflammatory immune response. An increase in NK cells is also associated with exhausted CD8+ T cells.

Beckmann added that one of those regulators, TBX21, is a promising therapeutic target because it serves as a master coordinator of the transition of CD8+ T cells from effective to exhausted.

Mount Sinai’s work on MIS-C represents the first gene-expression study from the hospital’s COVID-19 Biobank. Created through the work of a volunteer team of more than 100 nurses, doctors, and researchers, the repository serves as the backbone of Mount Sinai’s rapidly expanding COVID-19 research.

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