HVEM-LIGHT signaling promotes antibody-dependent neutrophil FcγR-mediated trogocytosis against herpes simplex virus infection

Matthew S. Gromisch; Masayuki Kuraoka; Carl F. Ware; Steven C. Almo; Betsy C. Herold

doi:10.1172/JCI203771

HVEM-LIGHT signaling promotes antibody-dependent neutrophil FcγR-mediated trogocytosis against herpes simplex virus infection

Matthew S. Gromisch,¹ Masayuki Kuraoka,² Carl F. Ware,³ Steven C. Almo,⁴ and Betsy C. Herold¹

Published June 4, 2026 - More info

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Abstract

Studies with a candidate vaccine deleted in glycoprotein D (ΔgD-2) for herpes simplex virus (HSV) prevention uncovered a role for herpes virus entry mediator (HVEM) in mediating antibody-dependent cell-mediated killing (ADCK) of virally-infected cells. Antibodies elicited by ΔgD-2 passively protect wild-type but not Fc gamma receptor (FcγR) or HVEM knockout (KO) mice. The goals of this study were to identify which cells mediate ADCK and the role of HVEM signaling. Using HVEM ligand and conditional cell-type specific HVEM KO mice combined with in vitro mouse and human cytolytic assays, we demonstrate that ADCK of HSV-infected cells is mediated primarily by neutrophils and requires their expression of HVEM and its ligand, LIGHT. Cytolysis is not associated with granzyme and perforin production but occurs by a trogocytosis-like pathway. Pharmacological inhibition of myosin light-chain kinase (MLCK), which mediates trogocytosis, inhibits cytolysis. Similar results were obtained when human neutrophils were cocultured with HSV-infected cells opsonized with ADCK-containing human immune serum or with breast cancer cells treated with an anti-HER2 trogocytosis mediating antibody. Killing was significantly reduced when an MLCK inhibitor or blocking antibodies to CD16a, HVEM, or LIGHT were added. Together these results define a mechanism of HVEM-enhanced FcγR-mediated neutrophil-dependent ADCK of targets cells.

HVEM-LIGHT signaling promotes antibody-dependent neutrophil FcγR-mediated trogocytosis against herpes simplex virus infection

Matthew S. Gromisch,¹ Masayuki Kuraoka,² Carl F. Ware,³ Steven C. Almo,⁴ and Betsy C. Herold¹

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HVEM-LIGHT signaling promotes antibody-dependent neutrophil FcγR-mediated trogocytosis against herpes simplex virus infection

Matthew S. Gromisch,1 Masayuki Kuraoka,2 Carl F. Ware,3 Steven C. Almo,4 and Betsy C. Herold1

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Matthew S. Gromisch,¹ Masayuki Kuraoka,² Carl F. Ware,³ Steven C. Almo,⁴ and Betsy C. Herold¹