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
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
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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; Gras, Stephanie; Ladell, Kristin et al. (2017) A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene. Immunity 47:835-847.e4|
|Slütter, 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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|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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