# Elucidation of Human Natural Killer Cell Development

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $356,850

## Abstract

This proposal focuses on elucidation of the processes regulating human natural killer (NK) cell development.
Our specific aims are: 1) To define the microenvironment(s) and characterize the regulation of NK cell
differentiation in human secondary lymphoid tissues (SLT); and 2) To define the order, regulation, and
phenotypic impact of major histocompatibility complex molecule binding receptor (MBR) acquisition during
human NK cell maturation.
NK cells are innate lymphoid cells (ILC) that have direct cytotoxic function against cancer cells. NK cells play a
vital role in immune surveillance against malignant transformation by complementing T cell immunity, and they
can mediate an important graft-versus-leukemia effect in the setting of allogeneic hematopoietic stem cell
transplantation for acute myeloid leukemia (AML). Our overall goal in this proposal is to gain a comprehensive
understanding of the cellular and molecular components that regulate human NK cell development and
function in order to best understand how they work and can be enhanced in the face of malignancy.
In particular, in Aim 1 we will define the cellular microenvironment(s) within SLT in which human NK cell
developmental intermediates (NKDI) reside and differentiate. We previously identified and characterized the
full spectrum of NKDI in these tissues. Over the past five years, additional and closely-related ILC subsets
have been discovered and characterized, and we have preliminary data to indicate that all ILCs derive from
a common ILC progenitor population that is naturally restricted to SLT. We hypothesize that the cellular milieu
within SLT influences NK cell differentiation from the common ILC progenitor, and we propose a series of
experiments to test our hypothesis and also to elucidate the mechanism(s) by which SLT-derived “helper” cell
populations influence this pathway. The goal of these studies is to identify new therapeutic targets to boost
immune function in the post-transplant setting for AML.
In Aim 2 we have preliminary data that suggest that NK cell functional maturation occurs in a stepwise
fashion associated with the orderly and coordinated acquisition of the activation receptor, NKp80, and two
types of MBRs: CD94/NKG2A and killer immunoglobulin-like receptors (KIR). What is not yet known and will
be tested in our proposed experiments is how this orderly acquisition of receptors is regulated and in turn how
signaling through the receptors themselves influences NK cell functional maturation. The clinical importance of
these studies lies in the fact that each of these surface NK cell receptors has the potential to be targeted for
immune checkpoint regulation in order to enhance NK cell-mediated immune therapy against cancer.

## Key facts

- **NIH application ID:** 10091309
- **Project number:** 5R01CA208353-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** AHARON G FREUD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,850
- **Award type:** 5
- **Project period:** 2017-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10091309

## Citation

> US National Institutes of Health, RePORTER application 10091309, Elucidation of Human Natural Killer Cell Development (5R01CA208353-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10091309. Licensed CC0.

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