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NK Cell and Monocyte Dysfunction in Multisystem Inflammatory Syndrome in Children
Jenna K Dick1,2, Jules A Sangala1,2, Venkatramana D Krishna3
1Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota Medical School, Minneapolis, MN.
Abstract:
Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multiorgan involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong Ab production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 wk postinfection. Therefore, we hypothesized that dysfunctional cell-mediated Ab responses downstream of Ab production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, whereas NK cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Taken together, our results reveal dysregulation in Ab-mediated cellular responses of myeloid and NK cells that likely contribute to the immune pathology of this disease.
Insights
Multisystem inflammatory syndrome in children (MIS-C) involves immune cell dysfunction. Researchers found that while monocytes were hyperfunctional, Natural Killer (NK) cells showed impaired killing and cytokine production, potentially impacting viral clearance.
Area of Science:
- Immunology
- Pediatric Infectious Diseases
- Cellular Biology
Background:
- Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection.
- MIS-C involves multiorgan inflammation and aberrant immune responses.
- Understanding cellular immune dysfunction in MIS-C is crucial for effective treatment.
Purpose of the Study:
- To investigate cellular immune responses, specifically cell-mediated antibody (Ab) functions, in children with MIS-C.
- To explore the role of dysfunctional cellular immunity in delayed viral product clearance.
- To identify potential therapeutic strategies targeting immune cell defects in MIS-C.
Main Methods:
- Ex vivo testing of cellular functions, including phagocytosis, cytokine production, and cytotoxicity.
- Analysis of Natural Killer (NK) cell exhaustion markers and correlation with Interleukin-6 (IL-6) levels.
- In vitro experiments using cellular engagers targeting CD16 and SARS-CoV-2 proteins to assess NK cell function rescue.
Main Results:
- Monocytes in MIS-C patients exhibited hyperfunctional phagocytosis and cytokine production.
- NK cells displayed hypofunctional killing and cytokine production, linked to an exhaustion signature and elevated IL-6.
- Cellular engagers demonstrated potential to restore NK cell function in vitro.
Conclusions:
- Dysregulation in Ab-mediated cellular responses involving myeloid and NK cells contributes to MIS-C immune pathology.
- Impaired NK cell function may hinder viral product clearance in MIS-C.
- Targeting NK cell dysfunction presents a potential therapeutic avenue for MIS-C.
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