The lung is a major portal of entry for many devastating human pathogens including respiratory viruses, such as the SARS corona virus and avian influenza viruses. Therefore, it is critical to develop vaccines that specifically induce long-lasting protective immunity in the respiratory tract. However, a significant hurdle in the development of pulmonary vaccines is our poor understanding of cell-mediated immunity in the lung. To fill this gap in our knowledge, we have undertaken a detailed analysis of the recall response to respiratory virus infections in the mouse model. Our data demonstrate that distinct subpopulations of memory CD8+ T cells contribute to the early and late stages of the recall response in the lung. The early phase of the recall response is mediated by non-proliferating memory CD8+ T cells that are rapidly recruited to the lung airways by inflammatory signals during the first few days of infection. These cells play a key role by limiting viral replication until activated effector cells start to arrive. However, in contrast to activated effector T cells, there is almost nothing known about the mechanisms that drive the recruitment of circulating, non- dividing memory T cells into the tissues or into inflammatory sites. Therefore, in the current application we will determine how the early stages of a T cell mediated recall response are regulated. First, we will identify the mechanisms that regulate memory T cell trafficking during a recall response by analyzing the specific roles of chemokines and chemokine receptors. Second, we will build on this information to determine whether inflammatory stimuli can be utilized to boost protective immunity elicited by either systemic or mucosal vaccination. Together, these studies will identify the mechanisms that regulate cellular immune responses in the respiratory tract and will be important for the development of vaccines that promote effective immunity to respiratory pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI076499-05
Application #
8204990
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Lapham, Cheryl K
Project Start
2008-01-01
Project End
2012-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$460,647
Indirect Cost
$215,622
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
Brincks, Erik L; Roberts, Alan D; Cookenham, Tres et al. (2013) Antigen-specific memory regulatory CD4+Foxp3+ T cells control memory responses to influenza virus infection. J Immunol 190:3438-46
Rudraraju, Rajeev; Surman, Sherri L; Jones, Bart G et al. (2012) Reduced frequencies and heightened CD103 expression among virus-induced CD8(+) T cells in the respiratory tract airways of vitamin A-deficient mice. Clin Vaccine Immunol 19:757-65
Kohlmeier, Jacob E; Reiley, William W; Perona-Wright, Georgia et al. (2011) Inflammatory chemokine receptors regulate CD8(+) T cell contraction and memory generation following infection. J Exp Med 208:1621-34
Kohlmeier, Jacob E; Connor, Lisa M; Roberts, Alan D et al. (2010) Nonmalignant clonal expansions of memory CD8+ T cells that arise with age vary in their capacity to mount recall responses to infection. J Immunol 185:3456-62
Kohlmeier, Jacob E; Cookenham, Tres; Roberts, Alan D et al. (2010) Type I interferons regulate cytolytic activity of memory CD8(+) T cells in the lung airways during respiratory virus challenge. Immunity 33:96-105
Takamura, Shiki; Roberts, Alan D; Jelley-Gibbs, Dawn M et al. (2010) The route of priming influences the ability of respiratory virus-specific memory CD8+ T cells to be activated by residual antigen. J Exp Med 207:1153-60
Sandau, Michelle M; Kohlmeier, Jacob E; Woodland, David L et al. (2010) IL-15 regulates both quantitative and qualitative features of the memory CD8 T cell pool. J Immunol 184:35-44
Kohlmeier, Jacob E; Cookenham, Tres; Miller, Shannon C et al. (2009) CXCR3 directs antigen-specific effector CD4+ T cell migration to the lung during parainfluenza virus infection. J Immunol 183:4378-84
Kohlmeier, Jacob E; Woodland, David L (2009) Immunity to respiratory viruses. Annu Rev Immunol 27:61-82
Kohlmeier, Jacob E; Miller, Shannon C; Smith, Joanna et al. (2008) The chemokine receptor CCR5 plays a key role in the early memory CD8+ T cell response to respiratory virus infections. Immunity 29:101-13