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CD4 T cell intrinsic signaling defects during viral exhaustion

Award Number: R21AI157121
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: 02/25/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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CD4 T cell intrinsic signaling defects during viral exhaustion - Project Summary: Chronic stimulation through the T cell receptor (TCR) drives T cells to progressively lose their ability to exert their effector functions in a process termed exhaustion. T cell exhaustion occurs during both cancer and persistent infections contributing to the failure of the adaptive immune response to control the tumor or infection. CD8 T cell exhaustion was initially described during chronic lymphocytic choriomeningitis virus (LCMV) infection. However, CD4 T cells control the delicate balance between the maintenance of effector CD8 T cell responses versus the development of CD8 T cell exhaustion during chronic infection. Despite their critical role in maintaining the antiviral CD8 T cell response, much less is known about the specific signaling defects and metabolic changes that occur within exhausted CD4 T cells. Gene expression studies examining LCMV-specific CD4 T cells have indicated that hundreds of genes are differentially expressed between CD4 T cells isolated during an acute versus chronic LCMV infection and that these genetic changes are different for CD4 T cells versus CD8 T cells. Many of the differentially expressed genes in CD4 T cells are related to TCR signaling and metabolic pathways, but how these alterations lead to specific defects in TCR signaling and cellular metabolism has not been defined. Our long-term goal is to understand the mechanisms that mediate CD4 T cell dysfunction during chronic viral infections and cancer progression. The objective of this application is to determine the specific defects in CD4 T cell signaling and metabolic pathways that develop during chronic LCMV infection. Our central hypothesis is that virus-specific CD4 T cells develop multiple defects in critical signaling pathways downstream of the TCR and metabolic pathways, resulting in the impaired ability of the CD4 T cell to mediate effector activity and proliferate during a chronic viral infection. Our hypothesis is based our own preliminary data, in conjunction with published genetic studies, indicating that expression of multiple signaling and metabolic proteins are reduced in virus-specific CD4 T cells following a persistent LCMV Clone 13 infection. The rationale for the proposed research is that, once the principal signaling and metabolic defects affecting exhausted CD4 T cells are identified, new and innovative therapeutic approaches can be targeted to restore CD4 T cell effector activity and enhance clearance of chronic viral infections and human cancers. We will achieve the goals of this proposal by pursuing the following two specific aims: 1) Examine the effects of viral exhaustion on early TCR signaling and function in CD4 T cells and 2) Investigate the impact of viral exhaustion on metabolism in CD4 T cells. The completion of these aims will determine if T cell exhaustion after infection with a chronic virus results in CD4 T cell intrinsic changes in the signaling capacity and metabolic function that would impact effector functions. Our results will provide insight into the molecular mechanism of CD4 T cell exhaustion and highlight potential avenues to modulate either signaling or metabolism to enhance the function of exhausted CD4 T cells during either chronic viral infection or cancer immunotherapy.


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	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	2	5/8/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	2	1/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $193,125 )
2022	2022	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	2	1/18/2022	NON-COMPETING CONTINUATION	$193,125
														Subtotal = $193,125

Issue Date FY: 2021 ( Subtotal = $231,750 )
2021	2021	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Allergy and Infectious Diseases Research	000	1	2/25/2021	NEW	$231,750
														Subtotal = $231,750

Grand Total All Awards = $424,875

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CD4 T cell intrinsic signaling defects during viral exhaustion

Award Number: R21AI157121

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: 02/25/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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