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Dick JK, Sangala JA, Krishna VD, Khaimraj A, Hamel L, Erickson SM, Hicks D, Soigner Y, Covill LE, Johnson AK, Ehrhardt MJ, Ernste K, Brodin P, Koup RA, Khaitan A, Baehr C, Thielen BK, Henzler CM, Skipper C, Miller JS, Bryceson YT, Wu J, John CC, Panoskaltsis-Mortari A, Orioles A, Steiner ME, Cheeran MCJ, Pravetoni M, Hart GT
J Immunol 213 (10) 1452-1466 [2024-11-15; online 2024-10-11]
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.
PubMed 39392378
DOI 10.4049/jimmunol.2400395
Crossref 10.4049/jimmunol.2400395
pmc: PMC11533154
pii: 267246