A new study of patients with Multisystem Inflammatory Syndrome in Children (MIS-C), a rare but severe complication of COVID-19 in children, reveals distinct immune features of COVID-19 not seen in adults that may clue scientists in to why SARS-CoV-2 infection manifests differently in children compared with adults. Their results showed that although the immune landscape in pediatric COVID-19 was similar to that in adults, MIS-C patients uniquely exhibited increased activation of a blood vessel-patrolling CD8+ killer T cell subset, and all pediatric COVID-19 patients harbored greater B cell frequencies for a more prolonged period of time than observed in healthy adults. MIS-C is characterized by pervasive inflammation, an array of symptoms ranging from fever to vomiting, and insufficient blood flow throughout the body that can lead to shock. To home into the immune features of MIS-C, Laura Vella and colleagues analyzed immune responses in blood taken from 30 hospitalized SARS-CoV-2-infected pediatric patients - 14 of whom were diagnosed with MIS-C. They compared results of this analysis with samples from adult COVID-19 patients, recovered adult COVID-19 subjects, and healthy adults. While MIS-C patients exhibited patterns of decreasing T cell count and activation similar to adults with severe COVID-19, they also exhibited robust activation of a killer T cell subset that patrols and interacts with the vasculature to control viral persistence. This feature was not observed in either adult or non-MIS-C pediatric COVID-19 patients. In addition, while children with COVID-19-driven acute respiratory distress syndrome had sustained immune activation, overall immune activation in MIS-C patients decreased over time, paralleling clinical improvement. All pediatric COVID-19 patients had substantially elevated B cell frequencies compared to healthy adults, but future work will be necessary to dissect how this impacts disease. Together, these findings portray the variability in immune responses to SARS-CoV-2 across ages and patient populations and may help inform treatments for severe COVID-19 in children.