Due to the emerging threat of epidemic and pandemic influenza virus (IAV), it is increasingly important to initiate informative studies that dissect the coordinated immune response to influenza virus infections. While much is known about the important role adaptive immune cells play in viral clearance and protection to subsequent infections, much less is understood about innate immunity and in particular, the contributions of dendritic cells (DC). Therefore our long-term goal is to determine how DC regulate mucosal immune responses and control the scope and outcome of respiratory infections. Our preliminary results show a novel regulation of IAV-specific CD8 T cells by DC within the lungs. This regulation is dependent upon cell-to-cell contact, MHC I, viral antigen, and IL-15 transpresentation. Without this interaction the IAV-specific CD8 T cell response is blunted and viral titers are increased leading to lethality. At this time the location of the DC:T cell interactions within the lungs and what additional DC derived factors and mechanisms are required for proper pulmonary CD8 and CD4 T cell responses remain unknown. Further, what role pulmonary DC play in immunity to intranasal IAV vaccines is unknown. Therefore in this proposal we will use our expertise in DC and pulmonary immune responses as well as our mouse model of IAV and other respiratory pathogens to determine how DC regulate pathogen specific T cell responses within the lungs in the following Specific Aims: 1) Determine the pulmonary location and kinetics of DC-T cell interactions and the requirements for individual DC subsets in pulmonary ectopic lymphoid tissue formation and maintenance, 2) Determine the requirements for rDC-mediated rescue of pulmonary IAV-specific T cell responses during IAV infections, 3) Determine the contribution of rDC to the induction and peripheral regulation of immunity to IAV vaccinations as well as during the peripheral regulation of T cell responses to other viral and bacterial respiratory pathogens. The knowledge gained from this study will not only be relevant to our understanding of the important underlying events required for effective immune responses and control of influenza-virus infections but also in the design of strategies to combat epidemic and pandemic influenza and other respiratory virus infections.

Public Health Relevance

While much is known about the roles CD8 T cells and B cells play in clearance of and protection from IAV infections, much less is understood about the roles that dendritic cells (DC) play in the early control of the infection and in the regulation of the IV-specific adaptive immune response. This project will determine how DC regulate pathogen-specific T cell responses during infection and vaccination. Understanding how pulmonary DC contribute to effective IAV immunity will not only improve our understanding of viral immunity, but also offer potential targets for vaccination against a globally important pathogen.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI071085-06A1
Application #
8642406
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Hauguel, Teresa M
Project Start
2006-07-01
Project End
2014-03-31
Budget Start
2013-04-10
Budget End
2014-03-31
Support Year
6
Fiscal Year
2013
Total Cost
$350,381
Indirect Cost
$115,381
Name
University of Iowa
Department
Pathology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Boonnak, Kobporn; Vogel, Leatrice; Feldmann, Friederike et al. (2014) Lymphopenia associated with highly virulent H5N1 virus infection due to plasmacytoid dendritic cell-mediated apoptosis of T cells. J Immunol 192:5906-12
Boyden, Alexander W; Frickman, Allison M; Legge, Kevin L et al. (2014) Primary and long-term B-cell responses in the upper airway and lung after influenza A virus infection. Immunol Res 59:73-80