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Trained immunity in group 2 innate lymphoid cells links neonatal to adult chronic lung disease.

Award Number: R03HL184975
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Trained immunity in group 2 innate lymphoid cells links neonatal to adult chronic lung disease. - Project Summary: Group 2 innate lymphoid cells (ILC2s) were initially described as tissue-regulatory cells that orchestrate the type 2 (TH2) immune response to the alarmins IL-33 and IL-25. Recent studies have identified ILC2 memory- like subsets capable of trained immunity, also known as innate immune memory, but the transcriptional programs driving ILC2 activation, memory formation, and persistence in the neonatal lung remain poorly understood. These gaps obscure the connection between early lung injury and the development of chronic diseases such as chronic obstructive pulmonary disease (COPD). Building upon our intriguing findings from our career development award, we have made a significant discovery: alterations in the composition of the intestinal fungal and bacterial microbiome influence the recruitment and activation of lung ILC2s in a mouse model of bronchopulmonary dysplasia (BPD). In our neonatal hyperoxia-induced mouse model of BPD, which produces a COPD-like phenotype in adulthood, we found that IL-33-driven TH2 inflammation, combined with microbial dysbiosis, modulates ILC2 accumulation. Moreover, we have identified memory ILC2s (mILC2s) that persist into adulthood in our model, suggesting a lasting link between neonatal injury and later COPD development. This goal of this R03 proposal is to investigate how ILC2 memory is established in infancy and contributes to COPD pathogenesis in later life. Our central hypothesis is that perinatal IL-33-driven TH2 inflammation induces persistent mILC2s, which promote COPD progression upon subsequent exposure to TH2 inflammation. To test this hypothesis, we have designed two aims that build upon the foundation of the career development award and lay the groundwork for future independent research. Aim 1 will elucidate the transcriptional programs that drive innate immune memory formation in ILC2s during neonatal injury. Aim 2 will investigate the functional effects of ILC2 memory during the development of COPD. The neonatal origins of adult lung disease is a critical knowledge gap in our understanding of chronic lung disease. This study will provide new insights into how early-life inflammatory events, such as neonatal lung injury, shape innate immune memory and contribute to COPD. The data will inform future research focused on interrogating the molecular mechanisms of ILC2 memory and the characterization of ILC2 memory in human neonates. Ultimately, we aim to explore anti-IL-33 therapeutics, currently under development for COPD, as a therapeutic intervention to prevent severe BPD in premature infants.


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 = $222,750 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Lung Diseases Research	000	1	8/24/2026	NEW	$222,750
														Subtotal = $222,750

Grand Total All Awards = $222,750

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Trained immunity in group 2 innate lymphoid cells links neonatal to adult chronic lung disease.

Award Number: R03HL184975

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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