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 #
5R01AI076499-03
Application #
7745450
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
2010-01-01
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$465,300
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
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Perona-Wright, Georgia; Kohlmeier, Jacob E; Bassity, Elizabeth et al. (2012) Persistent loss of IL-27 responsiveness in CD8+ memory T cells abrogates IL-10 expression in a recall response. Proc Natl Acad Sci U S A 109:18535-40
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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
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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

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