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TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection

Award Number: R01AI137248
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: 01/17/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection - Project Summary Because of their elevated frequency, ability to self-renew and rapid acquisition of effector function following re-activation, memory T cells have an enhanced ability to protect from secondary challenge. The generation of memory T cells is the focal point of numerous vaccine and immunotherapeutic strategies. Most (90-95%) effector T cells die after pathogen clearance, but those fated to become memory cells can be identified during the primary effector response, showing that activated T cells receive differentiation cues during the primary response to infection that influence memory fate differentiation. We have recently shown that T cell receptor (TCR) signals play a key role in driving CD4+ memory T cell differentiation. TCRs that are able to engage MHC Class II-bound antigen (pMHCII) in sustained interactions are biased towards the formation of long-lived memory, while TCRs that engage in short-lived interactions with antigen are biased towards terminal effector cell differentiation. We will build on those studies by using diverse infectious models to define aspects of the TCR-dependent activation and transcriptional program that leads to the formation of lymphoid-resident, circulating and tissue-resident CD4+ memory T cells. We pose three key questions. First, what is the role of TCR signal strength in the formation of memory T cells? We will explore the hypothesis that increasing TCR signal strength in vivo drives terminal effector T cell differentiation, while weaker TCR signal strength allows memory T cell formation. Second, what are the TCR binding parameters associated with memory T cell development? We will measure 2D affinity and bond lifetime with the application of force for TCRs at that are effector-biased or memory-biased. We will test the hypothesis that bond lifetimes will predict TCR-dependent memory differentiation. Third, what are the transcriptional programs that control memory formation? We will test the mechanistic role of molecules that are differentially expressed in memory T cell precursors during the primary effector response, including TCF-1. We anticipate that resolution of the questions posed in this study will provide a framework for determining in greater mechanistic detail how memory T cells form and identify therapeutic approaches for directly modulating CD4+ effector and memory T cell differentiation in vivo.


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: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	5	8/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $482,688 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	5	11/18/2021	NON-COMPETING CONTINUATION	$482,688
														Subtotal = $482,688

Issue Date FY: 2021 ( Subtotal = $482,688 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	4	12/15/2020	NON-COMPETING CONTINUATION	$482,688
														Subtotal = $482,688

Issue Date FY: 2020 ( Subtotal = $497,938 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	001	3	3/6/2020	NON-COMPETING CONTINUATION	$0
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	3	12/27/2019	NON-COMPETING CONTINUATION	$497,938
														Subtotal = $497,938

Issue Date FY: 2019 ( Subtotal = $513,188 )
2019	2019	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	2	12/3/2018	NON-COMPETING CONTINUATION	$513,188
														Subtotal = $513,188

Issue Date FY: 2018 ( Subtotal = $510,138 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Allergy and Infectious Diseases Research	000	1	1/17/2018	NEW	$510,138
														Subtotal = $510,138

Grand Total All Awards = $2,486,640

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TCR-dependent activation, functional differentiation and memory formation of CD4+ T cells following infection

Award Number: R01AI137248

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: 01/17/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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