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Optimizing functional synergies between local and systemic memory CD4 T cell responses to influenza

Award Number: R21AI148882
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Summary/Abstract Protective memory CD4 T cell responses against influenza A virus (IAV) involve a diverse array of cell types with unique characteristics. An emerging axis of heterogeneity is the division between lung tissue-resident memory (TRM) and conventional memory cells that circulate through secondary lymphoid organs. Most studies to date have focused on characterizing the anti-viral activities of these subsets in isolation during recall responses. Our preliminary studies, however, support the concept that synergies between regional and systemic memory cells are a vital and uncharacterized aspect of highly effective CD4 T cell responses. Our work also indicates that such integrated responses can be optimized to improve viral control and to reduce immunopathology by promoting different functions in TRM versus in conventional memory CD4 cells. This proposal will provide novel mechanistic insight into how vaccines can maximize synergies between local and systemic CD4 memory cells to improve vaccine-induced protection against IAV. We will optimize models to reconstitute naive mice with separate populations of well characterized lung TRM and/or conventional memory CD4 cells primed by IAV. This experimental system will facilitate clear analysis of how TRM responses impact the re-activation and subsequent response parameters of systemic memory CD4 cells upon IAV infection. Our models will also allow for modulation of the numbers and functional capacities of the cells within each memory compartment in order to identify unique subset-specific correlates of protection. We will also specifically deplete CD4 TRM in IAV-immune mice, thus allowing further characterization of local and systemic memory CD4 synergy during heterosubtypic infection in intact, vaccinated mice. In Aim 1, we will test the hypothesis that lung CD4 TRM activation within the first few days of IAV infection increases efficiency of antigen presentation in secondary lymphoid organs, leading to the more rapid recall of conventional memory CD4 cells. We will also determine if TRM reduce the magnitude of conventional memory responses through their earlier control of viral titers and inflammation in the lung. In Aim 2, we will determine how the integrated memory CD4 response affects key parameters of IAV clearance and collateral damage versus in mice reconstituted with either memory subset alone. Finally, we will determine if synergistic CD4 protection against IAV can be improved by restricting prototypical T-bet-dependent Th1 programming to only the TRM subset. This work will provide a mechanistic framework to improve CD4 T cell-dependent protection against IAV and other pathogens and optimize innovative experimental systems to facilitate future discovery.


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: 2022 ( Subtotal = $186,404 )
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	2	11/9/2021	NON-COMPETING CONTINUATION	$186,404
														Subtotal = $186,404

Issue Date FY: 2021 ( Subtotal = $224,404 )
2021	2021	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Allergy and Infectious Diseases Research	000	1	12/10/2020	NEW	$224,404
														Subtotal = $224,404

Grand Total All Awards = $410,808

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Optimizing functional synergies between local and systemic memory CD4 T cell responses to influenza

Award Number: R21AI148882

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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