PEPTIDES/MHC I COMPLEXES AND CD8+ T CELLS

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In this ongoing study of murine CD8 T lymphocytes our emphasis will shift from studying them ex vivo, as clones in long-term culture, to studying them in mice, their natural habitat. In making the transition, we will focus on developing immunogens and immunization strategies that stimulate naive CD8 cells to become effector cells, primarily cytotoxic T lymphocytes (CTL). To develop such "CD8 vaccines", having the possibilities for application in large human populations, our emphasis will be on immunogens that contain proteins or large protein fragments that can end up in the proper antigen-processing pathway of antigen- presenting cells. DNA vaccines are currently promising for this purpose. Heath shock fusion proteins have recently emerged as possible alternative candidates. A major aim will be to carry out comparative studies of DNA vaccines and heat shock fusion proteins, both having (or encoding) the same polypeptide precursor of a potent octapeptide agonist for the antigen-specific receptor of a well studied CD8 T cell clone (2C). Starting with transgenic mice expressing this receptor (2C TCR), we will analyze the response of their 2 TCR+ cells to these immunogens in various mice, including adoptive transfer recipients of the cells from transgenic donors. Other studies will concentrate on i) elucidating the basis for the unusual immunogenic properties of heat shock fusion proteins, ii) developing a tumor model for tracking the mobility and distribution in mice of CD8 T cells whose TCR recognizes peptide-MHC complexes on the tumor cells, and iii) comparing TCR affinity on live 2C cells, some having and some not having CD8 co-receptor molecules.