The respiratory tract serves as a significant entry point for pathogens including many potential bioweapons. Among these pathogens, Influenza virus represents a serious public health threat not only with regard to epidemic influenza but also because of the increasing threat of pandemic outbreaks. Previous studies have shown that protection from lethal influenza virus infections is mediated in part by CDS T cell killing of influenza-infected cells. The induction, magnitude, and effector phenotype of this T cell response in turn is generally thought to be intimately linked to the dendritic cell (DC) response to virus challenge. However our current understanding of how DC specifically regulate respiratory T cell responses in general and responses to lethal (highly virulent) and sub-lethal influenza virus infections in particular is quite limited. Therefore our long-term goal is to understand the mechanisms through which DC regulate, dependent upon the nature of the pulmonary challenge, the CDS T cell response to pulmonary infections. Through such regulation, DC appear to ultimately determine the outcome of virulent influenza virus infections as our preliminary results show that influenza-specific CDS T cell responses are inhibited during lethal dose influenza virus infections. This inhibition is dependent upon FasL expression by lymph node DC (LNDC) and LNDC driven apoptosis of the developing T cell response. Therefore in this proposal we will continue to utilize our mouse model of influenza virus infection to determine how DC regulate influenza-specific CDS T cells responses following lethal and sublethal influenza virus infections in the following Specific Aims: 1) Determine which LNDC subset(s) mediate LNDC elimination of virus-specific CDS T cell responses following lethal influenza virus infections and if this elimination is antigen-specific 2) Determine the mechanisms regulating IL-12p40 dependent LNDC FasL expression 3) Determine the role of DC in the initiation of virus-specific CDS effector responses during lethal and sublethal influenza infections. This proposal will elucidate how DC regulate and control the influenza-specific CDS T cell response during lethal and sublethal influenza virus infections. Furthermore it will yield important insights into the DC regulatory mechanisms that will need to be inhibited during vaccinations and treatments aimed at enhancing protective pulmonary immunity, particularly during lethal influenza virus infections and vaccinations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071085-03
Application #
7596897
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Salomon, Rachelle
Project Start
2007-04-15
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$357,025
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
Carlin, Lindsey E; Hemann, Emily A; Zacharias, Zeb R et al. (2018) Natural Killer Cell Recruitment to the Lung During Influenza A Virus Infection Is Dependent on CXCR3, CCR5, and Virus Exposure Dose. Front Immunol 9:781
Hemann, Emily A; Sjaastad, Louisa E; Langlois, Ryan A et al. (2016) Plasmacytoid Dendritic Cells Require Direct Infection To Sustain the Pulmonary Influenza A Virus-Specific CD8 T Cell Response. J Virol 90:2830-7
Hemann, Emily A; Legge, Kevin L (2014) Peripheral regulation of T cells by dendritic cells during infection. Immunol Res 59:66-72
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
Hemann, Emily A; Kang, Sang-Moo; Legge, Kevin L (2013) Protective CD8 T cell-mediated immunity against influenza A virus infection following influenza virus-like particle vaccination. J Immunol 191:2486-94
Boyden, Alexander W; Legge, Kevin L; Waldschmidt, Thomas J (2012) Pulmonary infection with influenza A virus induces site-specific germinal center and T follicular helper cell responses. PLoS One 7:e40733
Zhao, Jincun; Zhao, Jingxian; Legge, Kevin et al. (2011) Age-related increases in PGD(2) expression impair respiratory DC migration, resulting in diminished T cell responses upon respiratory virus infection in mice. J Clin Invest 121:4921-30
Case, Adam J; McGill, Jodi L; Tygrett, Lorraine T et al. (2011) Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge. Free Radic Biol Med 50:448-58
McGill, Jodi; Van Rooijen, Nico; Legge, Kevin L (2010) IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection. J Exp Med 207:521-34
VanoOsten Anderson, Rebecca; McGill, Jodi; Legge, Kevin L (2010) Quantification of the frequency and multiplicity of infection of respiratory- and lymph node-resident dendritic cells during influenza virus infection. PLoS One 5:e12902

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