# A novel pathway of Th17/Th2 induction: The role of cAMP signaling in DC

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $719,797

## Abstract

Abstract
Th2 and Th17 are two major arms of adaptive immunity involved in protective and pathological
responses. The range of their immune-mediated pathologies includes allergic diseases (Th2),
Crohn’s disease (Th17), multiple sclerosis (Th17) and psoriasis (Th17). Despite the introduction
of biologics such as anti-cytokines Abs, more effective and low-cost therapies are not yet
available. We have identified a new pathway that regulates both Th2 and Th17 differentiation by
cAMP levels in dendritic cells (DC). In this MPI RO1 application entitled: “A novel pathway of
Th17/Th2 induction - the role of cAMP signaling in DC” we propose that exploring the underlying
mechanisms and signaling events mediated through the G proteins; Gαs (Gnas) and Gαi
(Gnai2), which stimulate and inhibit cAMP synthesis, respectively, can provide the foundation
for such new therapies. The inhibition of this pathway (low cAMP) provokes Th2-inducing DC
(pro-Th2 DC), and its activation (high cAMP) induces Th17-inducing DC (pro-Th17 DC). We
generated two genetic mouse models; GnasΔCD11c that develop spontaneous Th2 bias and
Gnai2ΔCD11c that develop a Th17 bias responses. We recently identified that different cAMP
inducers regulate the expression levels of transcription factors in cDC2 cells that provoke
Th17/Th2 differentiation such as interferon regulatory factor 4 (IRF4), IRF5, Kruppel-like factor 4
(KLF4) and Notch2. Here we shown that different cAMP inducers regulate the expression levels
of these factors and switch the subsequent Th bias, which has led us to propose that the cDC2
cells represent a plastic DC subpopulation and that the cAMP levels dictate whether the cDC2
have a pro-Th17 and pro-Th2 bias. Hence, in this application we will explore and dissect the
following topics: In SA1 - we will analyze whether increasing cAMP by genetic deletion of Gnai2
in DC causes a Th17-associated immunopathology overtime, in SA2 – we will determine and
test the transcriptional network that defines the phenotypic pro-Th17 or pro-Th2 cDC2
subpopulations, in SA3 - we will test whether GPCR agonists (i.e., β2AR agonists) that increase
cAMP levels, provoke Th17-driven neutrophilic asthma, and in SA4 - we will identify and
functionally test novel pro-Th17 or pro-Th2 mediators produced by DC cells. In summary - our
discovery that cAMP regulates the pro-Th2 and pro-Th17 inducing properties of cDCs has led to
the identification of new pathway of Th2/Th17 regulation. The results will provide new insights
into the plasticity of cDC2 and Th2- and Th17- biasing. It has the potential to advance basic
immunological research and establish the basis for novel and innovative immunotherapeutic
strategies.

## Key facts

- **NIH application ID:** 10331024
- **Project number:** 5R01HL141999-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Eyal Raz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $719,797
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10331024

## Citation

> US National Institutes of Health, RePORTER application 10331024, A novel pathway of Th17/Th2 induction: The role of cAMP signaling in DC (5R01HL141999-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10331024. Licensed CC0.

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