NK cells require immune checkpoint receptor LILRB4/gp49B to control neurotropic Zika virus infections in mice

Lee, Ha-Na; Manangeeswaran, Mohanraj; Lewkowicz, Aaron P.; Engel, Kaliroi; Chowdhury, Monica; Garige, Mamatha; Eckhaus, Michael A.; Sourbier, Carole; Ireland, Derek D. C.; Verthelyi, Daniela

doi:10.1172/jci.insight.151420

Title: NK cells require immune checkpoint receptor LILRB4/gp49B to control neurotropic Zika virus infections in mice

Journal Article · Tue Feb 08 00:00:00 EST 2022 · JCI Insight

DOI:https://doi.org/10.1172/jci.insight.151420· OSTI ID:1843905

;

; Engel, Kaliroi;

; Garige, Mamatha; Eckhaus, Michael A.; Sourbier, Carole;

; Verthelyi, Daniela

Immune cells express an array of inhibitory checkpoint receptors that are upregulated upon activation and limit tissue damage associated with excessive response to pathogens or allergens. Mouse leukocyte immunoglobulin like receptor B4 (LILRB4), also known as glycoprotein 49B (gp49B), is an inhibitory checkpoint receptor constitutively expressed in myeloid cells and upregulated in B cells, T cells, and NK cells upon activation. Here, we report that expression of LILRB4, which binds Zika virus (ZIKV), was increased in microglia and myeloid cells infiltrating the brains of neonatal mice with ZIKV-associated meningoencephalitis. Importantly, while C57BL/6 mice developed transient neurological symptoms but survived infection, mice lacking LILRB4/gp49B (LILRB4 KO) exhibited more severe signs of neurological disease and succumbed to disease. Their brains showed increased cellular infiltration but reduced control of viral burden. The reduced viral clearance was associated with altered NK cell function in the absence of LILRB4/ gp49B. In naive animals, this manifested as reduced granzyme B responses to stimulation, but in ZIKV-infected animals, NK cells showed phenotypic changes that suggested altered maturation, diminished glucose consumption, reduced IFN-γ and granzyme B production, and impaired cytotoxicity. Together, our data reveal LILRB4/gp49B as an important regulator of NK cell function during viral infections.

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Research Organization:: Oak Ridge Inst. for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC); U.S. Food and Drug Administration (FDA)

Grant/Contract Number:: SC0014664

OSTI ID:: 1843905

Alternate ID(s):: OSTI ID: 1905017

Journal Information:: JCI Insight, Journal Name: JCI Insight Vol. 7 Journal Issue: 3; ISSN 2379-3708

Publisher:: American Society for Clinical InvestigationCopyright Statement

Country of Publication:: United States

Language:: English

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