The HHV-6B U20 Glycoprotein Inhibits NK Cell Responses By Binding ULBP1 And Blocking NKG2D Activation
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Dissertation
Authors
Weaver, GrantFaculty Advisor
Lawrence SternAcademic Program
Immunology and MicrobiologyDocument Type
Doctoral DissertationPublication Date
2023-04-06Keywords
human herpesvirusmajor histocompatibility protein
immunoevasion
structure prediction
MHC1b
natural killer cell
natural killer cell ligand
immune recognition
U20
ULBP1
NKG2D
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Many viruses impede host immune responses by downregulating class I MHC molecules (MHC-I), hindering antigen presentation to CD8+ T cells. Hosts will often counter this through NK cells that sense the absence of MHC-I and kill the infected cell. Human Herpesvirus 6B (HHV-6B) has also been shown to downregulate MHC-I but this does not result in NK-mediated elimination of the virus. Previous work has shown that HHV-6B downregulates three NK-activating stress ligands: MICB, ULBP1, and ULBP3. More recently, the U20 glycoprotein of HHV-6A was implicated in the downregulation of ULBP1 but the precise mechanism remains undetermined. We set out to better understand the role of HHV-6B U20 in modulating NK cell activity. We performed structural modeling studies that suggest that U20 is likely a viral nonclassical MHC (vMHC). These vMHCs are common tools used by herpesviruses to modulate host immune responses. Through in vitro studies with recombinant protein, we demonstrate that U20 binds directly to ULBP1 with sub-micromolar affinity (225nM). Transduction of U20 decreases NKG2D binding to ULBP1 at the cell surface but does not decrease ULBP1 protein levels (at the surface or in toto). Soluble U20 has the same effect and can also inhibit activation of ULBP1-stimulated primary NK cells. When taken together, these data suggest that U20 helps to downregulate NK cell activity by binding ULBP1, masking it from recognition by NKG2D at the surface of infected cells, resulting in a decrease in antiviral NK cell activation and killing.DOI
10.13028/mz9d-2f34Permanent Link to this Item
http://hdl.handle.net/20.500.14038/52009Rights
Copyright © 2023 WeaverDistribution License
https://creativecommons.org/licenses/by-nc/4.0/ae974a485f413a2113503eed53cd6c53
10.13028/mz9d-2f34