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Molecular basis for contrasting programs of fetal and adult T cell development

Award Number: R01HD100039
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Molecular basis for contrasting programs of fetal and adult T cell development - Project Summary T cells are generated in the thymus from gestation through much of the lifespan in mice and humans, and in some ways the products of fetal and postnatal T cell development are highly similar. However, there are several distinct waves of precursors that enter the T-cell program from mid-gestation to puberty, and successive waves make T cells with distinctive, specific differences in their developmental kinetics and qualitative lineage outputs. First-wave fetal thymocytes, for example, generate unique innate lymphoid cell subsets (ILCs) as well as T cells, give rise to unique gd T cell subsets, limit their diversity of T-cell receptor (TCR) gene rearrangements, and differentiate quickly, reaching early maturation milestones in a fraction of the time of postnatal thymocytes. In all these ways they differ from postnatal thymocytes. Importantly, these differences in T-cell development are not only observed in vivo, where the thymic structure itself is undergoing changes, but also, when they differentiate in a common microenvironment, as distinct waves of precursors maintain most of their unique developmental features in vitro in cocultures with Notch ligand-presenting stromal cells (e.g. OP9-DLL1). Thus, fetal and adult precursors are intrinsically programmed to differentiate with strikingly different kinetics and some differences in pathway, despite many similar outputs. Our goal is to determine the regulatory mechanisms that endow the cells with these different versions of the T-cell program. This proposal is for a renewal of a systems biology grant that focused on identifying T-cell developmental speed controllers. Our goal now is to determine how these and other mechanisms may be responsible for ontogenic control of T cell program differences. It is based on new results from our recent single-cell transcriptome analyses, ATAC-seq analyses, in vitro differentiation studies, and novel views of the cells’ regulatory states using specialized transgenic reporter mouse strains. We focus on three proposed mechanisms to explain the difference between first-wave fetal and postnatal precursors: the potential role of genome-wide chromatin states and accessibility; the role of transcription factor Meis1; and the potential modulation of differentiation by a select group of other regulatory factors. We will exploit novel knock-in fluorescent reporter mouse strains to identify previously unidentified developmental branchpoints unique to the first-wave fetal T-cell precursors. In addition, we will use lineage tracing to track whether the cells that give rise to the most fetal-unique descendants also give rise to conventional postnatal-type T cells or whether the fetal thymus is populated by a mosaic of precursors with different lineage biases. Our aims will be: (1) To determine the chromatin states across the genome that distinguish fetal and postnatal T cell precursors (2) To define the impact of Meis1 and select additional trans-acting factors on fetal T cell development (3) To determine whether common or distinct lineage precursors give rise to conventional vs. fetal-restricted cell fates, and to determine the developmental branchpoints when lineage-biasing mechanisms are deployed.


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: 2025 ( Subtotal = $685,980 )
2025	2025	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	6	7/21/2025	COMPETING CONTINUATION	$685,980
														Subtotal = $685,980

Issue Date FY: 2023 ( Subtotal = $537,755 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	5	4/7/2023	NON-COMPETING CONTINUATION	$537,755
														Subtotal = $537,755

Issue Date FY: 2022 ( Subtotal = $537,755 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	4	5/2/2022	NON-COMPETING CONTINUATION	$537,755
														Subtotal = $537,755

Issue Date FY: 2021 ( Subtotal = $537,755 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	3	3/31/2021	NON-COMPETING CONTINUATION	$537,755
														Subtotal = $537,755

Issue Date FY: 2020 ( Subtotal = $548,731 )
2020	2020	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	4/9/2020	NON-COMPETING CONTINUATION	$548,731
														Subtotal = $548,731

Issue Date FY: 2019 ( Subtotal = $559,065 )
2019	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	1	7/15/2019	NEW	$559,065
														Subtotal = $559,065

Grand Total All Awards = $3,407,041

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Molecular basis for contrasting programs of fetal and adult T cell development

Award Number: R01HD100039

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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