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The developmental layers in the CD8+ T cell response to chronic infection

Award Number: R01AI110613
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: 03/01/2014
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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The developmental layers in the CD8+ T cell response to chronic infection - Project Summary/Abstract Following infection, a small percentage of effector CD8+ T cells survive and transition into the long-lived memory pool. Given that memory CD8+ T cells are key to immunity against intracellular pathogens, it is essential that we understand the mechanisms by which they are formed. This question has been at the forefront of the field for decades. The current dogma suggests that a single lineage of naïve T cells can give rise to different short- and long-lived subsets of effector or memory T cells, depending upon the cues (inflammation, antigen) they encounter during infection. However, in the last funding cycle, we discovered that the propensity for T cells to adopt particular fates during infection is, instead, pre-programmed prior to infection, and is largely determined by their developmental origin. As all of our work to date has been performed in the context of acute infections, the major goal of our renewal proposal is to extend our studies to chronic infection, where we will determine how heterogeneity within the memory pool is linked to variation in the developmental origins of the responding cells. To accomplish this goal, we will combine our novel fate mapping system with the well-characterized mouse model of LCMV infection to dissect the functional heterogeneity within the memory pool. Our preliminary studies indicate that adult-derived cells preferentially become functionally exhausted during chronic infection compared to fetal-derived cells. However, clonal exhaustion of adult-derived CD8+ T cells can be prevented by overexpression of Lin28b, a master regulator of fetal-derived immune cells. Based on these findings and our published work, we hypothesize that the fate of CD8+ T cells during chronic infection is linked to their developmental origin. In the first aim, we will determine how developmental origin alters the CD8+ T cell response to chronic pathogens. In the second aim, we will examine how developmental origin alters gene regulatory programs in CD8+ T cells during chronic infection. In the last aim, we will determine how developmental differences in Lin28b influence the ability of CD8+ T cells to respond to chronic infection. Knowledge gained from these studies is expected to provide a better understanding of the mechanisms regulating the CD8+ T cell response to chronic pathogens, which is essential for developing more precise and effective strategies to restore functionality in exhausted CD8+ T cells.


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 = $0 )
2025	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	9	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $478,013 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	9	7/15/2022	NON-COMPETING CONTINUATION	$478,013
														Subtotal = $478,013

Issue Date FY: 2021 ( Subtotal = $478,013 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	8	7/16/2021	NON-COMPETING CONTINUATION	$478,013
														Subtotal = $478,013

Issue Date FY: 2020 ( Subtotal = $477,987 )
2020	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	002	7	7/14/2020	NON-COMPETING CONTINUATION	$477,987
2020	2019	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	001	6	3/28/2020	COMPETING CONTINUATION	$2,774
2020	2018	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	3/28/2020	NON-COMPETING CONTINUATION	-$2,774
														Subtotal = $477,987

Issue Date FY: 2019 ( Subtotal = $477,936 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	001	6	8/23/2019	COMPETING CONTINUATION	$477,936
2019	2018	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	8/23/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $477,936

Issue Date FY: 2018 ( Subtotal = $384,087 )
2018	2018	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	5	2/22/2018	NON-COMPETING CONTINUATION	$384,087
														Subtotal = $384,087

Issue Date FY: 2017 ( Subtotal = $384,253 )
2017	2017	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	4	2/14/2017	NON-COMPETING CONTINUATION	$384,253
														Subtotal = $384,253

Issue Date FY: 2016 ( Subtotal = $473,130 )
2016	2016	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	001	3	8/19/2016	NON-COMPETING CONTINUATION	$88,713
2016	2016	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	3	2/16/2016	NON-COMPETING CONTINUATION	$384,417
														Subtotal = $473,130

Issue Date FY: 2015 ( Subtotal = $540,476 )
2015	2015	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	001	2	7/28/2015	NON-COMPETING CONTINUATION	$155,900
2015	2015	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	2	2/10/2015	NON-COMPETING CONTINUATION	$384,576
														Subtotal = $540,476

Issue Date FY: 2014 ( Subtotal = $384,733 )
2014	2014	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	001	1	7/22/2014	NEW	$0
2014	2014	CORNELL UNIVERSITY	373 PINE ROAD	ITHACA	NY	14850	TOMPKINS	USA	Allergy and Infectious Diseases Research	000	1	2/14/2014	NEW	$384,733
														Subtotal = $384,733

Grand Total All Awards = $4,078,628

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The developmental layers in the CD8+ T cell response to chronic infection

Award Number: R01AI110613

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: 03/01/2014

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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