# Dendritic cell KLF2/Notch Axis and Th2 Responses to Eukaryotic Pathogens

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2020 · $394,129

## Abstract

Infection with eukaryotic pathogens places an enormous burden on the health of many species including
humans. Intracellular eukaryotic pathogens such as the dimorphic fungus, Histoplasma capsulatum (Hc), require
a T helper (Th) 1 response to promote elimination. Th2 that produce interleukin (IL)-4 and IL-13 override the
influence of Th1 and exaggerate the severity of infection to this fungus. While a Th2 response is detrimental to
Hc and other intracellular pathogens, it is vital for clearance of helminths. Activation of Th1 or Th2 requires
communication with dendritic cells (DCs). Knowledge regarding transcriptional regulators that license the latter
to promote a Th1 or Th2 response is incomplete. We have discovered that the transcription factor, Krüppel-like
factor (KLF) 2, in DCs calibrates the vigor of the Th2 response. A loss of KLF2 in DCs enhances release of IL-4
and IL-13 by Th2 and promotes accrual of these cells in lungs of Hc-infected mice. The net result is impaired
clearance of the fungus. The enhanced release of type 2 cytokines is dependent on an expansion of DCs that
express the Notch ligand, Jagged2. These preliminary data stimulated the central hypothesis that KLF2 is a key
element in DCs that limits the magnitude of Th2 responses and thus, differentially regulates the severity of
infection with Hc or with helminths. To test this hypothesis, we propose three Specific Aims. Aim 1 will elucidate
how KLF2-deficient DCs promote Th2 immunity. Studies will examine: 1) the influence of KLF2 on conventional
DCs in lungs and draining lymph nodes, 2) the impact on Th2 recruitment, survival, and/or proliferation and 3)
the role of DC KLF2 in controlling infection with a helminth. Specific Aim 2 will shift the focus to T cells and
examine the role of Notch receptors and Notch ligands on T cell function in Hc and helminth infection. Specific
Aim 3 will explore the genomic landscape regulated by KLF2 with a focus on the transcription factor hypoxia
inducing factor-1. In addition, we will open the aperture and perform RNA-seq and chromatin
immunoprecipitation (ChIP)-Seq to identify the KLF2-dependent gene networks in DCs that regulate Notch
signaling and Th2 accrual. A better understanding of the regulation of DCs by KLF2 during infection with
intracellular and extracellular pathogens protective could lead to the development of new therapies that govern
immunity to Hc and to helminths.

## Key facts

- **NIH application ID:** 9928351
- **Project number:** 5R01AI126818-05
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** GEORGE S. DEEPE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,129
- **Award type:** 5
- **Project period:** 2016-06-10 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928351

## Citation

> US National Institutes of Health, RePORTER application 9928351, Dendritic cell KLF2/Notch Axis and Th2 Responses to Eukaryotic Pathogens (5R01AI126818-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9928351. Licensed CC0.

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