# Transcriptional Regulation of Innate-Like T Cells

> **NIH NIH R37** · UNIVERSITY OF CHICAGO · 2023 · $204,253

## Abstract

Innate lymphocytes include ILCs and innate-like NKT/MAIT/gamma-delta T lymphocytes that
characteristically acquire Th1-, Th2- or Th17-like helper programs as well as tissue-resident properties
during development in the bone marrow or thymus. In that respect, they differ fundamentally from their
adaptive T cell counterparts, which are born naïve and recirculating, and only acquire tissue resident
effector properties after exposure to pathogens and cytokines. Our research focuses on understanding the
different mechanisms that control the parallel development of these populations in very different contexts.
While we previously reported that the transcription factor (TF) PLZF was a common signature of innate
lineages that directed their innate developmental fate, this project focuses on the layer of regulatory
enhancers that differentially control the helper lineage-specific TFs Gata-3, T-bet and RORgt in innate and
in adaptive lymphocytes, with emphasis on NK cells. We develop an epigenetic approach that identifies
these enhancers and we generate enhancer reporter strains that are used to specifically manipulate innate
and adaptive populations. The advantage of this approach is that epigenetic markers appear earlier and
are more stable than the TF that they regulate. They also provide more complexity and specificity to dissect
these developmental programs. In support of this approach, we recently identified a dedicated, ILC2-
specific enhancer and generated mice lacking this enhancer to dissect the respective contribution of innate
and adaptive type 2 responses in models of allergic airway inflammation. Here, we will apply this new
approach to elucidate the issues of identity and relationship between NK cells and other group I
lymphocytes, which express closely related properties and a degree of plasticity that have greatly
confounded prior studies. The specific aims will (SA#1) identify candidate enhancers of the NK
developmental pathway through a genome-wide bioinformatic search; (SA#2) validate these enhancers in
vivo through CRISPR deletions; (SA#3) generate enhancer-reporter strains that specifically identify and
manipulate NK cells. These studies will provide novel insights into the complexity and specificity of Group 1
Innate Lymphocytes, and generate new tools to probe their respective contributions in homeostasis and in
tumor, infection and autoimmune conditions.
RELEVANCE (See instructions):
Our studies investigate a recently uncovered population of so-called innate lymphocytes. These cells act
early in the immune response and provide major contributions in maintaining tissue health and in regulating
the response in tumors, infections, allergy and autoimmune conditions. Specifically, we develop new
genetic mouse models that will help define the differences between NK cells and ILC1s, two related
subtypes that exert potent but distinct contributions against tumors and viral infections in mouse and
human.

## Key facts

- **NIH application ID:** 10645070
- **Project number:** 5R37AI038339-27
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** ALBERT S. BENDELAC
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $204,253
- **Award type:** 5
- **Project period:** 1996-04-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10645070

## Citation

> US National Institutes of Health, RePORTER application 10645070, Transcriptional Regulation of Innate-Like T Cells (5R37AI038339-27). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10645070. Licensed CC0.

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