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Molecular Basis for γδ T Lineage Specification

Award Number: P01AI102853
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/15/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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Molecular Basis for γδ T Lineage Specification - Project 3 has been removed, but the overall scope of Projects 1, 2, and 4 have not been altered. Instead, the nature of the support provided by the leaders of Project 3 has been reduced and converted to paid consultation. Project 1: T lymphocytes comprise two major lineages,  and , which play critical, partially-distinct roles in host defense.  and  T cells arise from a common progenitor in the thymus; however, the molecular processes responsible for specification of these lineages during development in the thymus remain incompletely understood and this represents a major gap in knowledge. We seek to address this knowledge gap. In doing so, we have provided compelling evidence that specification of the  and  T cell fates is controlled by differences in T cell receptor (TCR) signal strength. These signaling differences regulate fate by proportional induction of Id3, which causes graded repression of the function of E box DNA binding proteins (E proteins; E2A and HEB). Nevertheless, the targets through which these E proteins regulate  T lineage commitment and effector fate specification remain unclear, and this presents a major gap in knowledge. To address this knowledge gap, we (Projects 1/2/4) employed a comprehensive, genome-wide approach, which revealed a number of important insights into the mechanism by which strong TCR signals remodel E protein binding to specify fate. First, strong TCR signals have selective effects on E proteins, markedly repressing E2A binding to the genome, while preserving HEB binding. The sparing of HEB binding is important because HEB function is required for development of interleukin-17 (IL-17) producing  T cells (Proj1/2/4). Second, we have identified Tcf7/TCF1 as both a novel E protein target and a critical cofactor that cooperates with E proteins in controlling  lineage commitment. Consequently, in the current proposal we seek to address two major questions relating to how E proteins control TCF1 expression and the targets through which they cooperate to control lineage fate. We will do so according to two aims: Aim1 seeks to interrogate the mechanism by which 3 critical E protein bound elements (EPE) near the Tcf7 locus regulate Tcf7/TCF1 expression and whether individual E protein family members (E2A, HEBCan, and HEBAlt) play distinct roles. In Aim 2, we will focus on the E/TCF targets through which the  lineage fate is facilitated. We have determined that many of the E/TCF co-bound targets regulate cell metabolism and  lineage commitment is coupled with changes in lipid composition. We will employ a series of gain and loss of function strategies to explore the importance of these targets in regulating  lineage commitment and peripheral effector fate. In addition, we will profile at a genome-wide scale how the reduction in TCF1 expression caused by strong TCR signals cooperates with E protein remodeling to specify the  lineage fate. We will do so using a novel method termed STARR-Seq (with Project 2 and Core B) that interrogates the regulatory element repertoire at a genome-wide scale in single cells. Consequently, in the current proposal, we integrate the expertise of all Project leaders (1, 2, and 4) and the Genomics Core to elucidate the mechanistic basis by which changes in E protein binding controls  lineage commitment and adoption of the IL-17 effector fate and determine how the molecular remodeling in mouse model systems aligns with that during development of human  T cells (Proj2). Project 2: The critical role played by γδ T cells in host defense and immunopathologies has been well-established and the unique features of γδ T cells are being harnessed for emerging cellular therapies. While there has been much effort in characterizing mouse γδ T cell development, very little is known about the regulatory mechanisms that control human γδ T cell selection and functional diversification into type 1 (IFN-γ+TBET+) and type 3 (IL-17+RORγT+) effector fates.


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 = $2,444,294 )
2025	2025	THE INSTITUTE FOR CANCER RESEARCH	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	11	8/18/2025	COMPETING CONTINUATION	$2,444,294
														Subtotal = $2,444,294

Issue Date FY: 2023 ( Subtotal = $1,980,932 )
2023	2023	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	10	7/21/2023	NON-COMPETING CONTINUATION	$1,980,932
														Subtotal = $1,980,932

Issue Date FY: 2022 ( Subtotal = $1,967,737 )
2022	2022	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	9	8/17/2022	NON-COMPETING CONTINUATION	$1,967,737
														Subtotal = $1,967,737

Issue Date FY: 2021 ( Subtotal = $2,004,349 )
2021	2021	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	8	8/5/2021	NON-COMPETING CONTINUATION	$2,004,349
														Subtotal = $2,004,349

Issue Date FY: 2020 ( Subtotal = $2,019,751 )
2020	2020	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	7	7/31/2020	NON-COMPETING CONTINUATION	$2,019,751
2020	2018	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	3/24/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,019,751

Issue Date FY: 2019 ( Subtotal = $2,144,459 )
2019	2019	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	6	8/5/2019	COMPETING CONTINUATION	$2,144,459
2019	2018	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	7/31/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,144,459

Issue Date FY: 2018 ( Subtotal = $1,792,662 )
2018	2018	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	4/30/2018	NON-COMPETING CONTINUATION	$1,792,662
														Subtotal = $1,792,662

Issue Date FY: 2017 ( Subtotal = $1,770,607 )
2017	2017	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	4/19/2017	NON-COMPETING CONTINUATION	$1,770,607
														Subtotal = $1,770,607

Issue Date FY: 2016 ( Subtotal = $1,799,772 )
2016	2016	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	4/12/2016	NON-COMPETING CONTINUATION	$1,799,772
														Subtotal = $1,799,772

Issue Date FY: 2015 ( Subtotal = $1,830,497 )
2015	2015	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	3/25/2015	NON-COMPETING CONTINUATION	$1,830,497
														Subtotal = $1,830,497

Issue Date FY: 2014 ( Subtotal = $1,861,695 )
2014	2014	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	1	8/8/2014	NEW	$167,400
2014	2014	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	5/15/2014	NEW	$1,694,295
														Subtotal = $1,861,695

Grand Total All Awards = $21,616,755

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Molecular Basis for γδ T Lineage Specification

Award Number: P01AI102853

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/15/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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