# RUNX:CBFb complex constrains fetal-restricted innate T cell generation from adult lymphopoietic progenitors

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $251,250

## Abstract

Summary
During intrauterine development the immune system generates cell subsets that will colonize mucosal barriers. This process
is restricted to a fetal/neonatal window as adult cells are unable to replenish mucosal lymphocytes. Despite this sharp
temporal constraint, the molecular mechanisms underpinning adult versus fetal hematopoietic potential has not been fully
elucidated. We propose that the expression of a specific set of fetal factors controlled by the dosage of the transcriptional
complex RUNX:CBF2 is responsible for the acquisition of fetal developmental potential. We made the unexpected
discovery that CBF2 haploinsufficiency confers adult hematopoietic stem cells the ability to reconstitute the prototypical
type 3 cytokine producing T17 cells. Transcriptional analysis of adult hematopoietic progenitors in CBF2 heterozygous
mice revealed the upregulation of genes usually active in embryos and likely controlled directly by RUNX:CBF2 complex.
We propose that an ensemble of transcription factors (TFs) central to embryonic hematopoiesis can instruct adult progenitors
to acquire fetal lymphopoietic potential. To test this hypothesis we will take advantage of the in utero transplantation assay
that faithfully recapitulate the fetal niche. Developmental assays of conventional or genetically altered precursors in utero
will help dissect the cellular and transcriptional requirements during the generation of mucosal innate-like lymphoid cells.
We also propose to exploit the developmental plasticity imposed by CBF2 haploinsufficiency to rewire adult regulatory
circuits in adult progenitors to adopt an embryonic developmental potential. Candidate fetal factors that are regulated by
RUNX:CBF2 will be overexpressed in adult progenitors for their ability to generate immune subsets with a restricted fetal
origin. In Aim 1, we will determine the overall chromatin landscape that characterizes CBF2 heterozygous adult
progenitors and permit enhanced reconstitution of fetal-type innate lymphocytes. In Aim 2, we will identify the genes
required for reprogramming adult hematopoietic progenitors towards fetal lymphopoietic potential. Our long term goal is
to map with high granularity transcriptional changes that license hematopoietic progenitors to give rise to tissue resident
fetal/neonatal-derived immune cells.

## Key facts

- **NIH application ID:** 10195780
- **Project number:** 1R21AI159457-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Joonsoo Kang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $251,250
- **Award type:** 1
- **Project period:** 2021-01-13 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10195780

## Citation

> US National Institutes of Health, RePORTER application 10195780, RUNX:CBFb complex constrains fetal-restricted innate T cell generation from adult lymphopoietic progenitors (1R21AI159457-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10195780. Licensed CC0.

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