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Harnessing type I interferon to promote lung-resident memory CD4 T cell immunity against influenza

Award Number: R01AI167994
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Harnessing type I interferon to promote lung-resident memory CD4 T cell immunity against influenza - Project Summary Memory CD4 T cells residing at sites of infection are key orchestrators of immunity. It is increasingly clear that key signals promoting such tissue-resident memory (TRM) cells do not overlap completely with those that support generation of conventional memory T cell subsets. Delineating signals that optimize CD4 TRM generation is important to improve vaccine-induced immunity against pathogens like influenza A virus (IAV) against which antibody alone cannot confer lasting protection. Our data indicates that type I interferons (IFN) can promote a unique activation module that optimizes the transition of anti-viral CD4 T cell effectors into TRM, and that Th1 programming, through the transcription factor T-bet, restricts the ability of cells to adopt this ‘pre-TRM’ effector state. This proposal will breakdown key mechanisms underlying the ability of type I IFN to promote lung CD4 TRM during IAV infection and in a translational model of intranasal vaccination. In Aim 1, we will use mouse models to differentiate how direct type I IFN signals to CD4 T cells, and indirect effects through modulating the inflammatory environment, impact the functional and transcriptional identity of pre-TRM effectors and ultimately shape the TRM landscape. We will also determine the extent to which T-bet expression by CD4 T cells effects the ability of I IFN to modulate TRM priming. In Aim 2, we will determine how IAV-primed CD4 T cells interpret type I IFN signals through signal transducer and activator of transcription (STAT) molecules, and the extent to which specific STAT activation signatures by type I IFN change through the kinetic window when we find memory fate to be determined. This analysis will be used to optimize strategies to boost TRM through increasing availability of type I IFN to responding CD4 T cells. A hallmark of effective CD4 TRM responses is their rapid activation which results in control of viral titers before systemic immune responses are initiated. As Type I IFNs have a suppressive impact on naive CD4 T cell activation, we propose that CD4 TRM are specialized to not only escape this suppressive impact during antigen encounter, but to harness type I IFN as an acute ‘trigger’ optimizing their recall. In Aim 3 we will determine the extent to which this mechanism operates, and how T-bet and specific STAT expression by TRM fine-tune this response. This proposal will provide high impact mechanistic data by elucidating how type I IFN can be harnessed to improve the generation and recall of CD4 TRM, with relevance to IAV and likely other respiratory pathogens. Our long-term goal is develop vaccine and therapeutic strategies incorporating insights from this research to improve durable and rapidly responsive cellular immunity in the lung.


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 = $378,652 )
2024	2024	THE UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	3	4/24/2024	NON-COMPETING CONTINUATION	$378,652
														Subtotal = $378,652

Issue Date FY: 2023 ( Subtotal = $378,652 )
2023	2023	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	2	4/25/2023	NON-COMPETING CONTINUATION	$378,652
														Subtotal = $378,652

Issue Date FY: 2022 ( Subtotal = $378,652 )
2022	2022	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	6/21/2022	NEW	$378,652
														Subtotal = $378,652

Grand Total All Awards = $1,135,956

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Harnessing type I interferon to promote lung-resident memory CD4 T cell immunity against influenza

Award Number: R01AI167994

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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