# Regulation of Nfil3 in innate lymphocyte-mediated host immunity

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $567,610

## Abstract

ABSTRACT
Innate lymphocytes represent early sentinels critical in host immunity against pathogens. The best studied
innate lymphocyte is the natural killer (NK) cell, which specifically targets virally-infected host cells. Humans
deficient in NK cells have severe health complications due to susceptibility to herpesvirus infections. In addition
to NK cells, a family of innate lymphoid cells (ILC) has recently been demonstrated to play an important role in
protection against pathogen infection at barrier surfaces such as the intestine, lung, and skin. Our long term
goals are to understand the the molecular mechanisms underlying the development of these innate
lymphocytes, which will increase our understanding of the function of these cells during infection. To this end,
we have recently identified a novel role for the transcription factor Nfil3 (also known as E4BP4) in development
of NK cells and all members of the ILC family. Using mouse pathogens that accurately model human infectious
diseases, along with newly-generated transgenic mouse models that ablate either the Nfil3 gene or
evolutionarily-conserved regulatory domains, this R01 grant proposes to investigate how Nfil3 is controling the
development and anti-pathogen functions of NK cells and ILCs. In Aim 1, we will investigate how Nfil3 is
transcriptionally regulated in innate lymphocyte progenitors by chromatin immunoprecipitation (ChIP) for the
transcription factors STAT5, PU.1, TCF-1, and Ets-1 followed by qPCR or deep sequencing (seq). In Aim 2, we
will use two novel mouse strains containing a CRISPR/Cas9-targeted deletion of conserved noncoding
sequences (termed Nfil3 CNS1 and CNS2) to determine the influence of intronic regulatory regions on innate
lymphocyte development and effector function against virus, helminth, and bacterial infection. In Aim 3, we will
use ChIP-seq, RNA-seq, and mass spectrometry to determine the genes that Nfil3 is controlling, and binding
partners that influence Nfil3-mediated regulation of these target genes. Together, the studies in this proposal
will not only increase our understanding of the general molecular mechanisms whereby NK cells and ILCs
develop and contribute to host defense during pathogen invasion, but also establish novel clinical paradigms
for how the innate lymphocyte compartment may be harnessed for therapeutic strategies against infectious
disease.

## Key facts

- **NIH application ID:** 10112809
- **Project number:** 5R01AI130043-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Joseph Chai-Yuen Sun
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $567,610
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112809

## Citation

> US National Institutes of Health, RePORTER application 10112809, Regulation of Nfil3 in innate lymphocyte-mediated host immunity (5R01AI130043-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10112809. Licensed CC0.

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