Influenza virus infections have a major impact on human health and the threat of pandemic infections remains imminent. Antibody inducing Influenza A virus (IAV) vaccines are available, however protection is suboptimal and requires annual reformulation of the vaccine. IAV can escape neutralization by preexisting antibodies due to the high rate of mutation in the primary targets of neutralization (hemagglutinin, HA and neuraminidase, NA) and due to its capacity to recombine in non-human hosts. In the absence of neutralizing antibodies, memory CD8 T-cell specific for epitopes located in conserved regions of IAV proteins like the internal components nucleoprotein (NP), polymerase A and matrix protein can confer protection. Recent human challenge studies and longitudinal analyses during the 2009 H1N1 IAV pandemic support the notion that cross-reactive memory CD8 T cells are capable of ameliorating disease when pre-existing antibodies are absent. As most humans carry a small number of these broadly protective memory CD8 T-cells, increasing the number of these cells through boosting is an attractive strategy to bolster their protective capacity. However, memory CD8 T-cells constitute a very heterogeneous population and little is known about how boosting or multiple antigen exposures effects CD8 T-cell mediated protection against IAV, For instance, we have recently reported that the type of booster agent significantly affects the localization and protective capacity of the resulting memory CD8 T-cell population (Sl?tter et al, 2013). Therefore, our long-term goal is to determine optimal memory CD8 T-cell characteristics for protection against IAV and to understand how such memory populations can be generated. In turn, these studies will provide crucial information to optimize broadly protective vaccines for IAV.
Specific Aim 1. Determine the molecular mechanisms regulating CXCR3 expression in memory CD8 T cells to enhance airway localization.
Specific Aim 2. Determine the impact of repetitive IAV infections on the generation of airway---surveilling, tissue resident and circulatin memory CD8 T cells and their relative contribution in protection from IAV.

Public Health Relevance

Influenza virus infections have a major impact on human health and the threat of pandemic infections remains imminent. Due to the ability of influenza to mutate and reassert, protection antibody inducting vaccines has limitations. Here, we will identify properties of memory CD8 T cells with the capacity to induce subtype transcending protection, information that will be crucial for the design of broadly protective vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI114543-05
Application #
9588831
Study Section
Immunity and Host Defense (IHD)
Program Officer
Lane, Mary Chelsea
Project Start
2014-11-01
Project End
2019-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
5
Fiscal Year
2019
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
Li, Fengyin; Zeng, Zhouhao; Xing, Shaojun et al. (2018) Ezh2 programs TFH differentiation by integrating phosphorylation-dependent activation of Bcl6 and polycomb-dependent repression of p19Arf. Nat Commun 9:5452
Martin, Matthew D; Badovinac, Vladimir P (2018) Defining Memory CD8 T Cell. Front Immunol 9:2692
Jensen, Isaac J; Sjaastad, Frances V; Griffith, Thomas S et al. (2018) Sepsis-Induced T Cell Immunoparalysis: The Ins and Outs of Impaired T Cell Immunity. J Immunol 200:1543-1553
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
Martin, Matthew D; Danahy, Derek B; Hartwig, Stacey M et al. (2017) Revealing the Complexity in CD8 T Cell Responses to Infection in Inbred C57B/6 versus Outbred Swiss Mice. Front Immunol 8:1527
Danahy, Derek B; Anthony, Scott M; Jensen, Isaac J et al. (2017) Polymicrobial sepsis impairs bystander recruitment of effector cells to infected skin despite optimal sensing and alarming function of skin resident memory CD8 T cells. PLoS Pathog 13:e1006569
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
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

Showing the most recent 10 out of 23 publications