Seasonal epidemics of the influenza virus result in 200,000 hospitalizations and 36,000 deaths each year in the United States. Current influenza vaccines elicit an antibody response against the surface glycoproteins. However, high mutation rates allow the influenza virus to evade neutralization by preexisting antibodies. Furthermore, influenza vaccines have greatly reduced effectiveness among the elderly population. Therefore, it is of critical importance to design a vaccine capable of providing long-lasting and broad protection against the influenza virus. A vaccine capable of inducing memory CD8 T cells has been of particular interest due to their ability to recognize epitopes from internal viral proteins that are highly conserved among strains. However, a CD8 T-cell based vaccine that provides lasting protection against flu has yet to be developed in part because there is insufficient knowledge of formation and maintenance of memory T cells in lung mucosa. This proposal seeks to provide insight into the signals necessary for the formation of lung resident memory T (TRM) cells that are thought to be capable of providing protection against the influenza virus. We hypothesize that CD4 help and an optimal balance of pro and anti-inflammatory signals is crucial for the formation of lung resident memory CD8 T cells.
Three specific aims are proposed to interrogate this hypothesis.
The first aim seeks to determine the requirement for CD4 help in the formation of lung resident memory through depletion of CD4 T cells. Chemokine and cytokine levels will be measured in the presence and absence of CD4 T cells to assess the mechanism of CD4 help.
The second aim will evaluate the importance of the TGF? and T-bet signaling axis in lung CD8 TRM cell formation and whether this pathway can control TRM formation through modulation of the degree of inflammatory exposure.
The third aim will determine the effect of aging on TRM formation and test the hypothesis that the increased inflammatory environment found in aged individuals acts leads to reduced formation of TRM cells. Altogether, this proposal seeks to provide insight into the signals necessary for TRM formation with the understanding that further knowledge of these signals will aid in the development of vaccines capable of providing long lasting protection against the influenza virus. In addition, this application details the applicant's training plan including research mentorship, advanced coursework, training in new techniques, and development of skills in scientific professionalism, writing, and presentation of data. The research and training outlined in this application will prepare the applicant to pursue a career in the conduct of clinically relevant research as an independent scientist.

Public Health Relevance

Infectious diseases such as influenza remain severe threats to public health with the elderly population especially vulnerable to these types of ailments. Understanding of the mechanisms by which the immune system can be harnessed to protect from these diseases is thus of critical importance in our ability to generate an effective vaccine. This proposal explores the signals required to generate memory T cells that reside within the tissues such as the lung and act as frontline protection against future infection.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Fuldner, Rebecca A
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Yale University
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New Haven
United States
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Laidlaw, Brian J; Craft, Joseph E; Kaech, Susan M (2016) The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol 16:102-11