The major focus of my lab is to investigate the mechanisms that control protective immunity to influenza and other respiratory virus infections. These pathogens are a major cause of human mortality every year. Cytotoxic T cells (CTL) play an important role in viral clearance and can provide short-term heterosubtypic immunity, indicating that they could be an effective target for vaccination. Unfortunately, cellular immunity to viral infections lasts only a few months even when large self-renewing populations of virus-specific memory CD8 T cells have been established. An important goal of my lab is to determine why protective cellular immunity declines so rapidly and why circulating memory T cells become ineffective at accelerating viral clearance during secondary challenge. Better understanding of the mechanisms that regulate T cell responses in vivo are likely to lead to more effective methods of vaccination against viruses and other pathogens that invade the respiratory tract. Transgenic mice, recombinant strains of influenza virus and MHC class I tetramer technology will be used to track CD4 and CD8 T cell response in vivo by flow cytometry and confocal microscopy. Influenza virus infection is largely limited to the respiratory tract, enabling us to analyze the local effects of a tissue-specific infection.

In a recent study, we showed that processed T cell antigens persist near the site of virus amplification in the lungs and draining lymph node for at least two months after influenza virus infection (Zammit et al.). Our data show that these processed T cell antigens have a profound influence on local T cell migration and activation in the lungs. Ongoing studies will investigate the effects of residual antigen presentation on memory T cells responses in vivo after influenza and other viral infections. These studies will include analysis of the antigen presentation pathways that are used during the different stages of the response. The effects of residual antigen presentation on adhesion molecules and other inflammatory mediators that influence local T cell migration will also be analyzed. Evidence suggests that T cell activation and location at the time of secondary viral challenge are likely to be important factors in protection. We will therefore investigate whether residual antigen presentation is an essential component of protective immunity.

Another long-term goal of my lab is to investigate how antibody responses influence, and potentially interfere with, T cell responses in immune animals. Preliminary data show that repeated pulmonary challenge with the same respiratory virus leads to extensive proliferation by virus-specific CD8 T cells in the draining lymph nodes, but little or no T cell response or local inflammation in the lungs. This study will investigate whether neutralizing antibodies redirect antigen presentation in the lungs to a pathway that is suppressive for T cell activation.

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