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Plasticity of Type 3 Innate Lymphoid Cells Regulated by Intestinal Microenvironment

Award Number: R01DK142104
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Plasticity of Type 3 Innate Lymphoid Cells Regulated by Intestinal Microenvironment - Project Summary/Abstract: (30 lines of text maximum) Innate lymphoid cells (ILC) are the innate counterparts of CD4+ T helper cells and are particularly abundant in mucosal tissues where they contribute to tissue immunosurveillance, immunoregulation, tissue repair, and the maintenance of homeostasis or tissue inflammation. Based on transcriptional regulation and cytokine profiles, three distinct types of ILCs have been proposed and identified: T-bet+ ILC1s that produce IFNg, GATA3+ ILC2s that secrete IL-5 and IL-13, and RORgt+ ILC3s that release IL-22 and IL-17A/F. However, ILC numbers and functions are believed to vary in a context-dependent fashion such that single-cell RNA-Seq and flow cytometry- based analyses including a range of markers have revealed high levels of ILC heterogeneity arising due to the plasticity of these cell populations. However, the molecular mechanisms and environmental cues governing this plasticity remain to be elucidated, in part due to a lack of appropriate animal models. We thus generated ILC3- specific reporter and Cre recombinase-expressing mice in which we identified GATA3+ exILC3s which were previously ILC3s but has converted into the ILC2s. Using this model, the goals of this study are to examine (1) the mechanistic basis for transdifferentiation between ILC3s and ILC2s and (2) the roles that these plastic ILCs play in vivo. To accomplish these goals, we have formulated two specific aims. In Aim 1, we seek to understand the environmental factors and mechanisms that regulate the maintenance of ILC3 identity and plasticity. Using ex vivo and in vivo models with fate mapping approaches, we will evaluate the environmental cues such as gut inflammation and gut damage associated with transdifferentiation and will elucidate the physiological roles of transdifferentiated cells during gut inflammation. By gathering phenotypic, transcriptomic, and chromatin accessibility data, we will capture the functional status and transdifferentiation potential of cells with distinct identities. While our supporting data clearly indicate that ILC3s can undergo conversion into ILC2s, when, where, and how ILC3s actively convert into ILC2s remain to be established. In Aim 2, we thus propose to elucidate the active conversion from ILC3s to ILC2s in response to tissue-specific factors under ILC2-intensive conditions and/or when the identity of ILC3s is decreased. To do this, we will adapt our ILC3-fate mapping mice to models of helminth infection and type 2 immunity-mediated colonic inflammation and will explore ILC3s conversion into ILC2s. We will also clarify the roles of GATA3+ exILC3s under steady-state conditions and in inflammatory settings. Through the conditional deletion of GATA3 only in the converted ILC2s from ILC3s or the reconstitution of ILC2-depleted mice with GATA3+ exILC3s or naturally generated ILC2s derived from their precursors in the bone marrow, we will interrogate their roles during helminth infection and type 2 immunity-mediated inflammation in the colon. These studies will advance our current understanding of ILC plasticity under specific circumstances. The insight gained from these analyses will better enable us to control the balance among ILCs in vivo, leveraging such plasticity under ILC-intensive settings of infection, inflammation, and the repair of intestinal damage.


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 = $713,084 )
2026	2026	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	4/1/2026	NON-COMPETING CONTINUATION	$713,084
														Subtotal = $713,084

Issue Date FY: 2025 ( Subtotal = $656,001 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	7/24/2025	NEW	$0
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/27/2025	NEW	$656,001
														Subtotal = $656,001

Grand Total All Awards = $1,369,085

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Plasticity of Type 3 Innate Lymphoid Cells Regulated by Intestinal Microenvironment

Award Number: R01DK142104

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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