Cytomegalovirus Protein US10 Selectively Regulates Expression of Human Leukocyte Antigen Class I Molecules

Core Concepts

The HCMV-encoded protein US10 selectively binds to and regulates the expression of different HLA-I allotypes in a multimodal manner, contributing to immune evasion.

Abstract

The study investigates the role of the HCMV-encoded protein US10 in modulating the expression of human leukocyte antigen class I (HLA-I) molecules, which are crucial for immune recognition by CD8+ T cells and NK cells.

Key findings:

• US10 binds to all HLA-I heavy chains, but the consequences of this binding are HLA-I genotype and allotype-specific.
• HLA-A allotypes are resistant to US10-mediated downregulation, while HLA-B, -C, -E, and -G show varying degrees of sensitivity.
• The level of HLA-B sensitivity to US10 correlates with the HLA-B allotype's dependence on the chaperone protein tapasin for efficient peptide loading.
• US10 can bind to HLA-C and -G in their β2m-assembled form, promoting their retention in the ER, while it reduces β2m-dimerization of some HLA-B allotypes.
• In HCMV-infected cells, US10 knockdown leads to increased surface expression of specific HLA-B allotypes, but not HLA-A, highlighting the selective nature of US10's effects.
• The study reveals the exceptional HLA-I selectivity of the HCMV-encoded US10 protein and its contribution to immune evasion through multimodal regulation of HLA-I expression.

Stats

HLA-A02:01 surface expression was not affected by US10 siRNA treatment in HCMV-infected cells.
Upregulation of HLA-B07:02 and HLA-B*44:02 was observed in HCMV ΔUS2-US6-infected cells upon US10 siRNA treatment.
US10 siRNA treatment led to increased HLA-I assembly and recruitment to the peptide loading complex in HCMV-infected cells.

Quotes

"US10 possesses a particular specificity for HLA-C and -G. It promotes their assembly with β2m and forms a stable complex with HC/β2m heterodimers."
"US10 binding to HLA-I prohibits recruitment to the PLC, which strongly affects cell surface expression of tapasin-dependent HLA-B allotypes."
"Since opposite to HLA-A/-B/-E, HLA-C and -G can strongly associate with US10 also in a W6/32-reactive conformation, β2m- and peptide-binding apparently does not in general induce US10- resistant conformations."

Key Insights Distilled From

Multimodal HLA-I genotype regulation by human cytomegalovirus US10 and resulting surface patterning

by Gerk... at www.biorxiv.org 01-13-2023

https://www.biorxiv.org/content/10.1101/2023.01.10.523457v1

Deeper Inquiries

How might the selective targeting of HLA-C and -G by US10 impact immune responses at the maternal-fetal interface during congenital HCMV infections?

The selective targeting of HLA-C and -G by US10 in the context of congenital HCMV infections could have significant implications at the maternal-fetal interface. HLA-C and -G are crucial in regulating interactions between maternal immune cells and fetal cells, particularly in the placenta. HLA-C is known to interact with killer cell immunoglobulin-like receptors (KIRs) on maternal NK cells, influencing their activity and preventing NK cell-mediated attack on the fetus. HLA-G, on the other hand, plays a key role in immune tolerance at the maternal-fetal interface by inhibiting maternal immune responses against the semi-allogeneic fetus.
By targeting HLA-C and -G, US10 may disrupt the delicate balance of immune tolerance and immune activation at the maternal-fetal interface. This could potentially lead to increased immune recognition of fetal cells by maternal immune cells, triggering inflammatory responses that could be detrimental to the developing fetus. Additionally, dysregulation of HLA-C and -G expression by US10 may impact the balance of immune checkpoints and regulatory mechanisms that are crucial for maintaining a healthy pregnancy.

How might the selective targeting of HLA-C and -G by US10 impact immune responses at the maternal-fetal interface during congenital HCMV infections?

The selective targeting of HLA-C and -G by US10 in the context of congenital HCMV infections could have significant implications at the maternal-fetal interface. HLA-C and -G are crucial in regulating interactions between maternal immune cells and fetal cells, particularly in the placenta. HLA-C is known to interact with killer cell immunoglobulin-like receptors (KIRs) on maternal NK cells, influencing their activity and preventing NK cell-mediated attack on the fetus. HLA-G, on the other hand, plays a key role in immune tolerance at the maternal-fetal interface by inhibiting maternal immune responses against the semi-allogeneic fetus.
By targeting HLA-C and -G, US10 may disrupt the delicate balance of immune tolerance and immune activation at the maternal-fetal interface. This could potentially lead to increased immune recognition of fetal cells by maternal immune cells, triggering inflammatory responses that could be detrimental to the developing fetus. Additionally, dysregulation of HLA-C and -G expression by US10 may impact the balance of immune checkpoints and regulatory mechanisms that are crucial for maintaining a healthy pregnancy.

How might the selective targeting of HLA-C and -G by US10 impact immune responses at the maternal-fetal interface during congenital HCMV infections?

The selective targeting of HLA-C and -G by US10 in the context of congenital HCMV infections could have significant implications at the maternal-fetal interface. HLA-C and -G are crucial in regulating interactions between maternal immune cells and fetal cells, particularly in the placenta. HLA-C is known to interact with killer cell immunoglobulin-like receptors (KIRs) on maternal NK cells, influencing their activity and preventing NK cell-mediated attack on the fetus. HLA-G, on the other hand, plays a key role in immune tolerance at the maternal-fetal interface by inhibiting maternal immune responses against the semi-allogeneic fetus.
By targeting HLA-C and -G, US10 may disrupt the delicate balance of immune tolerance and immune activation at the maternal-fetal interface. This could potentially lead to increased immune recognition of fetal cells by maternal immune cells, triggering inflammatory responses that could be detrimental to the developing fetus. Additionally, dysregulation of HLA-C and -G expression by US10 may impact the balance of immune checkpoints and regulatory mechanisms that are crucial for maintaining a healthy pregnancy.