# Natural Killer Cell Subpopulations in COPD Exacerbations

> **NIH VA I01** · CINCINNATI VA MEDICAL CENTER RESEARCH · 2024 · —

## Abstract

Despite decades of research, no effective therapies exist to circumvent the irreversible alterations in
lung function associated with COPD. Further, complications of COPD arise from acute and chronic
exacerbations that amplify ongoing injury and remodeling that increase morbidity and mortality. The
pathophysiology of exacerbations is poorly understood, but is primarily due to inflammation from infections.
Some patients are more susceptible to exacerbations and represent an `exacerbator phenotype' associated
with COPD-dependent changes in innate and adaptive immunity. Natural killer (NK) cells are a
heterogeneous population of lymphocytes that are important in the defense against infections. They are also
involved in initiating and directing active immune responses through cytokine production. NK cells recognize
pathogen-infected cells expressing ligands for an array of activating and inhibitory receptors. Research by
our lab and others identified multiple effects of smoking on NK cell function that suggest these changes are
significant in the pathophysiology of COPD exacerbations. Traditionally, NK cells were divided into immature
and mature subpopulations based on CD16 and CD56 expression. Recently, high-dimensional analysis of
NK cells revealed a surprisingly high degree of phenotypic diversity and that each individual has thousands
of unique populations of NK cells. Although the expression of various NK cell surface markers provides clues
about the function of subpopulations, the significance of each populations is unknown. Therefore, we probed
NK cell phenotypes from a cohort of non-smokers, smokers, and COPD patients targeting NK cell activating
and inhibitory receptors. These studies revealed several unique NK cell populations that differed between
groups. Further analyses showed that the size of NK cell subsets associated with a previous exacerbation
with 95% confidence. Based on these findings, we hypothesized that smoking alters NK cell heterogeneity
which leads to the emergence of unique populations that can serve as biomarkers of increased risk of COPD
exacerbations. We will test this hypothesis with the following Specific Aims: Aim 1: Define the natural history
of NK cell diversity and plasticity in never smokers and smokers. Previous analyses of NK cell populations
over time are based on limited phenotyping and high-dimensional analyses of NK cell populations have been
derived from a single time point. To advance our understanding of the heterogeneity of NK cell populations
over time, we will conduct a 3-year prospective longitudinal analysis of NK cell plasticity in never smokers
and current smokers without COPD. Aim 2. Define whether alterations in NK cell populations precede or
occur following exacerbations in COPD to determine the usefulness of NK cell phenotyping as a biomarker
of future exacerbations. Preliminary data identify alterations in NK cell subsets associated with COPD
exacerbations. However, we do not know if these al...

## Key facts

- **NIH application ID:** 10741797
- **Project number:** 5I01CX001891-08
- **Recipient organization:** CINCINNATI VA MEDICAL CENTER RESEARCH
- **Principal Investigator:** Michael Borchers
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10741797

## Citation

> US National Institutes of Health, RePORTER application 10741797, Natural Killer Cell Subpopulations in COPD Exacerbations (5I01CX001891-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10741797. Licensed CC0.

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