Program Director/Principal Investigator (Last, First, Middle): Harty, John T. Influenza infection is a major public health menace and our current strategies of seasonal influenza vaccination provide suboptimal protection. Thus, it is critical to provide basic, mechanistic insights into the possibility of universal influenza vaccines. In the absence of neutralizing antibodies, the presence of IAV-specific memory CD8 T cells targeting conserved viral proteins such as NP or M2, which are maintained systemically as well as in the lung correlate with control of viral titers and reduction of disease symptoms in humans. Mouse models confirm the potency of IAV specific memory CD8 T cells to provide strain-transcending heterosubtypic immunity, but also suggest it is the lung resident memory CD8 T cells (Trm) that enable swift and robust protection against IAV infection. Thus, establishing a robust long-term Trm population in the lung may be an important goal for an IAV vaccine. However, evidence from our own lab and others shows that lung Trm gradually wane in numbers with time, resulting in a loss of protective immunity. Our long-term goal is to understand the biology of IAV-induced Trm and how these cells can be manipulated to enhance immunity. We will address this long-term goal with the following specific aims:
Specific Aim 1. Dissect the metabolic and genetic factors underlying compromised Trm survival in the lung compared to skin.
Specific Aim 2. Determine if lung Trm can be efficiently restored by boosting and the consequences on lung physiology and protection from IAV.
Specific Aim 3. Visualize the dynamics of Trm responses to secondary infection in lung OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

Public Health Relevance

Harty, John T. Influenza infection is a major public health menace and our current strategies of seasonal influenza vaccination provide suboptimal protection. Thus, it is critical to provide basic, mechanistic insights into the possibility of universal influenza vaccines. Lung residing CD8+ T cells can provide potent immunity against influenza and our long-term goal is to understand the biology of influenza-induced T cells and how these cells can be manipulated to enhance immunity. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042767-21
Application #
9828040
Study Section
Immunity and Host Defense (IHD)
Program Officer
Kelly, Halonna R
Project Start
1998-04-01
Project End
2023-10-31
Budget Start
2019-11-01
Budget End
2020-10-31
Support Year
21
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Van Braeckel-Budimir, Natalija; Varga, Steven M; Badovinac, Vladimir P et al. (2018) Repeated Antigen Exposure Extends the Durability of Influenza-Specific Lung-Resident Memory CD8+ T Cells and Heterosubtypic Immunity. Cell Rep 24:3374-3382.e3
Shan, Qiang; Zeng, Zhouhao; Xing, Shaojun et al. (2017) The transcription factor Runx3 guards cytotoxic CD8+ effector T cells against deviation towards follicular helper T cell lineage. Nat Immunol 18:931-939
Van Braeckel-Budimir, Natalija; Gras, Stephanie; Ladell, Kristin et al. (2017) A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene. Immunity 47:835-847.e4
Sl├╝tter, Bram; Van Braeckel-Budimir, Natalija; Abboud, Georges et al. (2017) Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity. Sci Immunol 2:
Gullicksrud, Jodi A; Li, Fengyin; Xing, Shaojun et al. (2017) Differential Requirements for Tcf1 Long Isoforms in CD8+ and CD4+ T Cell Responses to Acute Viral Infection. J Immunol 199:911-919
Itani, Farah R; Sinha, Sushmita; Brate, Ashley A et al. (2017) Suppression of autoimmune demyelinating disease by preferential stimulation of CNS-specific CD8 T cells using Listeria-encoded neuroantigen. Sci Rep 7:1519
Osborn, Jossef F; Mooster, Jana L; Hobbs, Samuel J et al. (2017) Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8+ T cells. Sci Immunol 2:
He, Bing; Xing, Shaojun; Chen, Changya et al. (2016) CD8+ T Cells Utilize Highly Dynamic Enhancer Repertoires and Regulatory Circuitry in Response to Infections. Immunity 45:1341-1354
Kim, Marie T; Kurup, Samarchith P; Starbeck-Miller, Gabriel R et al. (2016) Manipulating Memory CD8 T Cell Numbers by Timed Enhancement of IL-2 Signals. J Immunol 197:1754-61
Kim, Marie T; Richer, Martin J; Gross, Brett P et al. (2015) Enhancing Dendritic Cell-based Immunotherapy with IL-2/Monoclonal Antibody Complexes for Control of Established Tumors. J Immunol 195:4537-44

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