# Characterization of CMV-specific T cell responses in immunocompromised hosts

> **NIH NIH K99** · DUKE UNIVERSITY · 2020 · $125,134

## Abstract

The most common infectious complication following organ transplantation is cytomegalovirus (CMV), resulting
in increased allograft rejection and mortality. Current virology research suggests that the presence of antigen-
specific “polyfunctional” T cells is essential for viral control; when encountering target, these rare cells are
capable of producing multiple inflammatory cytokines (e.g., IFNg, TNFa, IL-2) and effecting rapid cytolysis,
while those cells expressing only one (i.e., monofunctional) or no cytokines have been associated with
progressively less protection. Unfortunately, assays for quantification of polyfunctional T cells remains arduous
and lack inter-facility reproducibility; additionally, the mechanisms driving the generation and maintenance of
such cells remains unknown. My preliminary data in kidney transplant recipients reveals that those lacking
polyfunctional CMV responses are at increased risk of CMV reactivation. Importantly, I have also found that T
cell exhaustion is not primarily responsible for discrepancies in CMV-associated functionality observed
between patients with and without CMV reactivation, thereby suggesting alternative mechanisms. Therefore,
based on preliminary data, the central hypothesis tested is that STAT5- and myc-dependent molecular
reprogramming is necessary for the generation and maintenance of CMV-specific polyfunctional T cells, and
that expansion of cells with an IL-7-based protocol recapitulates this reprogramming and will produce
functional, long-lived cell-based therapies in the event of CMV reactivation. The proposed research will: (1)
determine if a transcriptional profile may be used not only to quantify polyfunctional T cells but also identify
SOT recipients at risk for CMV reactivation; (2) determine the critical role of STAT5 and myc activation and
alterative metabolic pathways expression on the function of CMV-specific polyfunctional T cells; and (3)
optimize cytokine-based protocols for the ex-vivo expansion of CMV-specific T cells by characterization of
functional, proliferative, and metabolic parameters. My primary career goal is to obtain a tenure-track position
and establish an independent research laboratory at a major biomedical institution. My long-term career goal is
to establish a career as an independently-funded physician-scientist, with a particular focus in transplant
immunology and associated changes in T cells metabolism. To achieve these goals, I will develop my
intellectual base, strengthen my leadership skills, and enhance the necessary technical skills through the
duration of the proposed study. Valuable training is readily available in the labs of Drs. Murdoch, Chao, and
Piantadosi. Furthermore, to promote and bolster my progress during the award period, I have organized a
scientific advisory committee of well-established scientists and clinicians with expertise in all areas of the
application. Collectively, the proposed research will enhance our understanding of th...

## Key facts

- **NIH application ID:** 9976049
- **Project number:** 1K99AI143927-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Zachary Ryan Healy
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $125,134
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976049

## Citation

> US National Institutes of Health, RePORTER application 9976049, Characterization of CMV-specific T cell responses in immunocompromised hosts (1K99AI143927-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976049. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*