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

Award Number: R01HL141999
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	4	5/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $719,797 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	4	1/10/2022	NON-COMPETING CONTINUATION	$647,817
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	001	4	6/13/2022	NON-COMPETING CONTINUATION	$71,980
														Subtotal = $719,797

Issue Date FY: 2021 ( Subtotal = $718,659 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	3	1/20/2021	NON-COMPETING CONTINUATION	$718,659
														Subtotal = $718,659

Issue Date FY: 2020 ( Subtotal = $717,520 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	001	2	1/31/2020	NON-COMPETING CONTINUATION	$35,876
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	2	12/21/2019	NON-COMPETING CONTINUATION	$681,644
														Subtotal = $717,520

Issue Date FY: 2019 ( Subtotal = $716,381 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Lung Diseases Research	000	1	12/23/2018	NEW	$716,381
														Subtotal = $716,381

Grand Total All Awards = $2,872,357

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

Award Number: R01HL141999

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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