Influenza infection is a recurring public health burden 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 and much work is devoted to strategies to induce broadly neutralizing antibodies. However, 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 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 with broad coverage. Recent evidence from our laboratories shows that repetitive encounter with influenza infection to generate quaternary (4M) memory in the lung profoundly improves the durability of lung Trm and heterosubtypic immunity compared to primary (1M) memory Trm. Our long-term goal is to understand the biology of IAV-induced Trm and how these cells can be manipulated to enhance immunity to aid in development of universal influenza vaccines. We will address this long-term goal with the following specific aims:
Specific Aim 1. Determine the mechanisms underlying improved durability of 4M vs 1M IAV-specific lung Trm Specific Aim 2. Determine if IAV-specific 4M lung Trm provide better per cell protection than 1M lung Trm Specific Aim 3. Dissect the role of 4M vs 1M IAV-specific CD69+CD103+ LN populations

Public Health Relevance

Influenza infection is a recurring public health burden and the need for better vaccines with that induce universal coverage is clear. To achieve this, basic studies of immunity to influenza in the lung are necessary. Lung residing CD8+ T cells targeting conserved antigens can provide potent, strain transcending immunity against influenza and our long-term goal is to understand how to generate and maintain these protective T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114543-07
Application #
10077814
Study Section
Immunity and Host Defense (IHD)
Program Officer
Lane, Mary Chelsea
Project Start
2014-11-01
Project End
2024-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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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:
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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; Martin, Matthew D; Hartwig, Stacey M et al. (2017) Antigen Exposure History Defines CD8 T Cell Dynamics and Protection during Localized Pulmonary Infections. Front Immunol 8:40
Cabrera-Perez, Javier; Badovinac, Vladimir P; Griffith, Thomas S (2017) Enteric immunity, the gut microbiome, and sepsis: Rethinking the germ theory of disease. Exp Biol Med (Maywood) 242:127-139
Martin, Matthew D; Shan, Qiang; Xue, Hai-Hui et al. (2017) Time and Antigen-Stimulation History Influence Memory CD8 T Cell Bystander Responses. Front Immunol 8:634

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