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Immunoregulatory Role of Conventional Dendritic Cell Type 2 in Allergic Lung Inflammation

Award Number: R01HL173152
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Immunoregulatory Role of Conventional Dendritic Cell Type 2 in Allergic Lung Inflammation - Project Summary Asthma is a chronic airway disease in which diverse immune cells participate in the development and eventual resolution of allergic lung inflammation. Among these immune cells, conventional dendritic cell type 2 (cDC2) plays a fundamental role in bridging innate and adaptive immunity. However, recent studies show that the cDC2 population is diverse and heterogeneous, unlike the more homogenous cDC1. Our group has characterized the heterogeneous cDC2 subsets with distinct transcriptomic features in the lung and demonstrated that a unique pro-inflammatory cDC2 subset, CSF1R+cDC2, is necessary for sensing inhaled allergens. Our supporting data for this proposal show that CX3CR1 is predominantly expressed by cDC2 but not cDC1 in mouse and human lungs, indicating that CX3CR1+cDC2 is another unique cDC2 subset. In mice, we compared the gene expression patterns between CX3CR1+cDC2 and their receptor-negative counterparts. Remarkably, the gene expression pattern of CX3CR1+cDC2 was skewed towards anti-inflammatory pathways. This corresponds with prior reports indicating an immunoregulatory role for CX3CR1 expressing myeloid cells, and our own published data showed that CX3CR1+ lung macrophages facilitated the resolution of allergic lung inflammation. This proposal aims to examine the mechanisms by which CX3CR1+cDC2 has the role of a contrasting anti-inflammatory role in allergic lung inflammation. To analyze the functions of the CX3CR1+cDC2, we generated several novel transgenic mice to deplete them selectively or knockout CX3CR1 in a cDC2- specific way. Our data show that depletion of CX3CR1+cDC2 results in a marked reduction in CD4+Foxp3+ regulatory T cells (Tregs) and the delayed resolution of allergic lung inflammation with delayed resolution. In addition, CX3CR1+cDC2 expressed higher levels of the co-inhibitory molecule PD-L1 compared to their receptor-negative counterparts. These data strongly suggest that lung CX3CR1+cDC2 is an anti-inflammatory subset of cDC2, which plays an essential role in the resolution of allergic lung inflammation. In this proposal, we will characterize the anti-inflammatory role of the lung CX3CR1+cDC2 subset and determine the immunologic mechanisms by which the CX3CR1+cDC2 regulates allergic lung inflammation. To do so, we will first determine whether CX3CR1+cDC2 drives Treg development. Next, we will characterize the molecular signalings via MHC classes and PD-L1, contributing to CX3CR1+cDC2-mediated anti-inflammatory function. Finally, we will seek to elucidate the human relevance of this unique lung cDC2 as an anti- inflammatory subset, using human BAL cells and intrathoracic lymph nodes obtained by bronchoscopy. In summary, these proposed experiments are designed to uncover a novel anti-inflammatory role of the CX3CR1+cDC2 subset in the resolution of asthmatic inflammation. These data will significantly expand the understanding of the processes involved in the resolution of allergic lung inflammation and delineate novel treatment options.


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: 2026 ( Subtotal = $730,764 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	2	3/24/2026	NON-COMPETING CONTINUATION	$730,764
														Subtotal = $730,764

Issue Date FY: 2025 ( Subtotal = $760,759 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Lung Diseases Research	000	1	5/14/2025	NEW	$760,759
														Subtotal = $760,759

Grand Total All Awards = $1,491,523

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Immunoregulatory Role of Conventional Dendritic Cell Type 2 in Allergic Lung Inflammation

Award Number: R01HL173152

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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