Tracking NK and Memory T Cell Dynamics in Children Affected by Multisystem Inflammatory Syndrome (MIS-C)

Background Multisystem inflammatory syndrome in children (MIS-C) is a severe condition that arises 4–6 weeks after SARS-CoV-2 exposure, marked by persistent fever, mucocutaneous symptoms, cardiac involvement, and shock. Natural killer (NK) cells are thought to contribute during the acute phase due to their antiviral and immunoregulatory roles, but their phenotype during recovery is not well defined. An expansion of TCR Vβ21.3+ T cells has been observed during acute MIS-C, though their long-term presence and significance remain unclear. Methods Peripheral blood mononuclear cells (PBMCs) were collected from 4 healthy pediatric controls, 4 febrile (non-COVID) controls, 4 children with acute COVID-19, 9 with acute MIS-C, 8 MIS-C convalescents (6–12 months), and 6 long-term MIS-C convalescents (4 years). TCR Vβ21.3 expression was analyzed using a T cell panel (CD3, CD4, CD8, CD27, CD45RA, TCR Vβ21.3). NK cell phenotype was assessed after co-culture with K562 cells using markers including CD56, CD3, CD16, CXCR6, Ki67, NKG2D, NKG2C, and CD158. Results NK cells from acute MIS-C patients showed decreased CD57, CD158, and CD107a, along with increased NKG2D expression. Clustering analysis revealed a unique NK cell population exclusive to acute MIS-C, defined by absent CD107a and elevated CXCR6 and Ki67. Most alterations resolved within 6–12 months, except CD158, which remained low even after 4 years. TCR Vβ21.3+ T cells persisted for up to a year but were undetectable at 4 years. Conclusions MIS-C triggers a transient NK phenotype marked by reduced cytotoxicity and increased activation, suggesting a hyperactivated or dysregulated immune profile. Persistent downregulation of the inhibitory receptor CD158 may indicate prolonged NK activation. TCR Vβ21.3+ T cells appear to be short lived. Further long-term studies with larger cohorts are needed to validate these findings.