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Molecular mechanisms of CD8 T cell fate decision instructed by cytokine signaling

Award Number: R01AI176664
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: 12/01/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Molecular mechanisms of CD8 T cell fate decision instructed by cytokine signaling - Abstract In response to viral infection or vaccination, antigen(Ag)-specific CD8 T cells that are present at low frequencies undergo rapid clonal expansion. While the majority of activated CD8 T cells become terminally differentiated effector T (T ECF) cells following expansion and die after Ag clearance, a small fraction of them persists as memory cells (Tr,1er,:) that contribute to long-term protection. However, it remains incompletely understood how cell-extrinsic stimuli through TCR and cytokine receptors establish the gene regulatory networks that determine the fates of activated CD8 T cells. The overall goal of this grant is to dissect the molecular and cellular mechanisms by which TCR and IL-2R signaling cooperatively regulates CD8 T cell differentiation through the control of the critical transcription factor TCF-1 encoded by Tcf7_ We will test the hypothesize that cooperative action between signals induced by antigen and IL-2, but not IL-15, specifically during priming induces expression of a set of transcription factors and epigenetic changes at a transcriptional silencer element in the Tcf7 locus. The establishment of stable Tcf7 repression requires the stimulationresponsive enhancement of IL-2R signaling, which establishes steady the TEFF- or T MEM-specific gene regulatory circuitry that can be stably maintained after the inducing cell extrinsic stimuli decays as immune responses resolve or become equilibrated. These studies will provide insights into the long standing question of the molecular mechanisms of CD8 T cell differentiation and potential application to programming improved immunotherapies.


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: 2026 ( Subtotal = $631,762 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	3	11/26/2025	NON-COMPETING CONTINUATION	$631,762
														Subtotal = $631,762

Issue Date FY: 2025 ( Subtotal = $566,110 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	2	1/16/2025	NON-COMPETING CONTINUATION	$566,110
														Subtotal = $566,110

Issue Date FY: 2024 ( Subtotal = $583,619 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	1	11/28/2023	NEW	$525,256
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$58,363
														Subtotal = $583,619

Grand Total All Awards = $1,781,491

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Molecular mechanisms of CD8 T cell fate decision instructed by cytokine signaling

Award Number: R01AI176664

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: 12/01/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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