# Natural Killer Cell Control of Murine Cytomegalovirus Infection

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $662,923

## Abstract

Abstract
Natural killer (NK) cells kill tumors and infected cells by integrating signals from two
functional types of receptors, activation and inhibitory. In the mouse, many of these receptors
belong to the Ly49 family, encoded by a cluster of highly related genes, discovered by the
applicant’s laboratory. The highly polymorphic Ly49 receptors are related to killer
immunoglobulin-like receptors (KIRs) on human NK cells as outstanding examples of
convergent evolution. The applicant’s laboratory previously showed that the Ly49H activation
receptor is responsible for genetic resistance of C57BL/6 mice to murine cytomegalovirus
(MCMV) infections. Ly49H recognizes a molecule encoded by MCMV, in a manner
independent of major histocompatibility complex class I (MHC-I) alleles. Studies from other
groups suggest that in non-C57BL/6 mice, other Ly49 activation receptors that are not alleles of
Ly49H appear to recognize MCMV-infected cells in vitro but their in vivo significance has not
been established. Ironically, a recent publication from the applicant’s lab also show that Ly49
inhibitory receptors can provide NK cell-mediated protection against MCMV. This process
depends on MHC-I alleles, via Ly49 inhibitory receptor-dependent licensing or education of NK
cells, and their capacity to detect loss of MHC-I expression, termed missing-self, during MCMV
infection. These studies provide the basis for understanding the association of human inhibitory
KIRs and their MHC-I ligands that are also paradoxically associated with protection from viral
infection, indicating that further studies may have clinical significance. But it has been
challenging to study these receptors further in vivo due to the complexities of the Ly49
receptors, including their polymorphism and variegated expression. Here the applicant
presents preliminary data in which expression of all Ly49s have been extinguished and can be
replaced by a single Ly49 expressed on all NK cells. This technological advance will facilitate
the further elucidation of how NK cells control MCMV infection. Thus, the Specific Aims of this
proposal are to: 1) Study non-Ly49H activation receptors in NK cell responses to MCMV. 2)
Characterize NK cells with inhibitory receptors mediating MCMV control. 3) Evaluate
interactions between Ly49 receptors in control of MCMV. Thus, these studies will provide new
insight into the mechanisms by which NK cells control viral infection.

## Key facts

- **NIH application ID:** 10444730
- **Project number:** 2R01AI131680-06A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Wayne M. Yokoyama
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $662,923
- **Award type:** 2
- **Project period:** 2017-09-25 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444730

## Citation

> US National Institutes of Health, RePORTER application 10444730, Natural Killer Cell Control of Murine Cytomegalovirus Infection (2R01AI131680-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444730. Licensed CC0.

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