Regulation of memory CD8+ T cell recruitment to the lung

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DESCRIPTION (provided by applicant): 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.