Lab Research Focus
Research in our laboratory is focused upon understanding how the immune response combats viral infections. We are particularly interested in elucidating how anti-viral CD8 T-cell responses are initiated, how they successfully resolve many viral infections, and why these responses are sometimes ineffective, thus promoting the establishment of persistent infections. One of the best experimental systems for analyzing CD8 T-cell responses is lymphocytic choriomeningitis virus (LCMV) infection of mice. Studies on the immune response to this virus have been extremely informative, providing the first evidence for CTL activity during virus infection and shaping our understanding of such fundamental concepts as MHC restriction and immunological memory.
Recently, our ability to dissect CD8 T-cell responses has been greatly enhanced by the development of MHC-class I tetramers. This exciting technology can be used to directly visualize antigen-specific T-cells without the requirement for reactivation in vitro. We extensively use tetramers to track CD8 T-cell responses during acute and chronic viral infections. We have shown that during acute LCMV infection CD8 T-cells undergo massive expansion and that at the peak of the response over 50% of the host's CD8 T-cells are virus-specific. Virus-specific CD8 T-cells are also elicited during chronic LCMV infection but, in this case, the infection is not rapidly resolved. Our studies have shown that this is due to the inability of virus-specific CD8 T-cells to sustain their effector activity and also due to T-cell deletion in the periphery. Additionally, this "immunological silencing" is more pronounced under conditions of CD4 T-cell deficiency. The next step is to determine the mechanisms underlying this silencing and to devise rational strategies for reactivating these cells. Overall, our work has broad implications for the development of vaccination and therapeutic strategies to control acute and chronic viral infections as well as tumor outgrowth.
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