# HCMV-induced innate-like CD8 T cells and allogeneic HCT outcome

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $759,700

## Abstract

PROJECT SUMMARY
Human cytomegalovirus (HCMV) infects all populations with a penetrance of 50-100% and is kept latent by
innate and adaptive surveillance. However, it is a significant cause of morbidity and mortality in conditions of
immune reconstitution and suppression, such as in neonates and recipients of solid organ or hematopoietic cell
transplants. The T cell response to HCMV through classical HCMV peptide-specific αβ cytotoxic T lymphocytes
has been well-studied, and the development of NKG2C+ natural killer cells in response to HCMV infection and
reactivation is under active investigation. In addition to these lymphocytes, however, large populations of αβ-
TCR CD8 T cells that express NKG2C and other NK-associated receptors have also been observed in HCMV-
seropositive healthy donors and patients. These innate-like NKG2C+ CD8 T cells appear to have broad activity
against AML and HCMV-infected cells, no activity against uninfected allogeneic fibroblasts, and reduced
expression of PD-1 in response to CD3 stimulation. RNAseq analysis has revealed that NKG2C+ CD8 T cells
have reduced expression of the transcription factor Bcl11b, critical for cutting off alternative innate fates during
the early thymic development of T cells. The central hypothesis of this proposal is that HCMV exposure induces
an NKG2C+ CD8 T cell population by diverting clonotypic T cells toward an innate fate through the
downregulation of Bcl11b, which alters TCR signaling and promotes alternative recognition pathways beneficial
to leukemia patients. The first aim of the proposal is to evaluate the T cell identity of members of the NKG2C+
CD8 T cell population (clonality, TCR specificity and signaling) and how their transcriptional and epigenetic
programs are altered from other CD8 T cells by Bcl11b loss. The second aim will assess the function of the NK-
associated activating and inhibitory receptors on the NKG2C+ CD8 T cells, with the goal of identifying the
mechanism behind their anti-tumor and anti-HCMV activity. Finally, in a collaboration with the Center for
International Blood and Marrow Transplantation, an extensive hematopoietic cell transplantation patient sample
bank and clinical database will be utilized to determine whether the post-transplantation emergence of an
NKG2C+ CD8 T cell population impacts the risk of leukemia relapse and overall survival. Together, the results
of these studies will elucidate not only the therapeutic potentials of this innate-like T cell population but also how
adaptive and innate fates can be bridged.

## Key facts

- **NIH application ID:** 10122518
- **Project number:** 1R01AI150999-01A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** KATHARINE C HSU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $759,700
- **Award type:** 1
- **Project period:** 2021-04-09 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122518

## Citation

> US National Institutes of Health, RePORTER application 10122518, HCMV-induced innate-like CD8 T cells and allogeneic HCT outcome (1R01AI150999-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10122518. Licensed CC0.

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