The primary focus of my research lab is on developing rational approaches for producing and evaluating effective vaccines, and my laboratory has established projects in murine, non-human primate, and human models that are linked by this goal. Vaccines work by establishing immune memory, and new generations of vaccines are being developed that specifically target CD8+ T cell responses. Each project in my laboratory takes advantage of the dramatic improvements in the quality of quantitative analysis of T cell immune responses provided by the new MHC tetramer assay [Altman, 1996 #436] and recently introduced single cell-based assays for peptide stimulated production of cytokines such as gamma interferon (4).

We use easily manipulable murine models to answer outstanding questions on the nature of T cell memory. We have shown that in mice the size of the memory pool is determined by the size of the acute immune response (4), confirming Doherty's "clonal burst" hypothesis. We have established systems in rhesus macaque and human models to determine if the observations in the murine system can be extended to primates. The development of the T cell memory lineage remains poorly understood, and our approach has been to focus on T cell repertoire development during the course of an immune response (6) to gain mechanistic insight into the establishment of memory repertoires. The phenotype of antigen-specific T cells has been shown to change over time (7,8), and Zinkernagel and colleagues have proposed that protective T cell memory not only requires high frequencies of antigen-specific memory cells but also that these cells retain the capacity to traffic into non-lymphoid tissues (9). The MHC tetramers permit phenotypic characterization of antigen-specific T cells (1), and we will attempt to correlate molecular analyses of cell surface markers with trafficking properties of memory T cells in murine, rhesus macaque, and human models.

Finally, we are using the new methods to better characterize the human CD8+ T cell response to HIV. Murine models have shown that during chronic infection, CD8+ T cells can be specifically silenced but not deleted (10). Inspired by this observation, we seek to determine the functional potential of the large pools of HIV-specific CD8+ T cells that we have detected in HIV-infected individuals (1,11) and we ask how the frequency and function of HIV-specific CD8+ T cells is affected by highly active antiretroviral therapy.

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11. Gray, C. M., et al. (1999). J. Immunol., 162, 1780-1788.