The Jon Yewdell Selection

My Top 5 | The Jon Yewdell Selection Courtesy of Jon Yewdell 1. In the now distant year of 1970, the physical nature of the plasma membrane (or any membrane for that matter) was uncertain. Frye and Edidin used Sendai virus to fuse human and mouse cell, then stained the cells with fluorochrome-labeled antibodies specific for human or mouse antigens.1 They watched the unfolding drama in a fluorescent microscope as the human and mouse proteins completely mixed in real time, providing an elegant, direct demonstration of the fluid nature of the plasma membrane and the ability of proteins to freely (more or less) diffuse in the membrane. This was one of the first scientific papers I read as an undergraduate in 1974, and certainly the first I understood. I still look to it as an example of the power of direct observation and the principle that simple experiments can provide profound answers. 2. The power of new techniques, even relatively simple ones, is clearly shown by Kohler and Milstein's 1975 demonstration of how to make cell lines that secrete monoclonal antibodies.2 Where would we be without monoclonal antibodies, which have had a huge impact on nearly every area of biomedical research and are coming into their own (finally) in the clinic? Personally, I would be doing something else, since I earned my PhD generating and characterizing monoclonal antibodies specific for viral proteins. This sparked my interest in protein folding, which as it turned out, is crucial to how proteins are processed into the short peptides recognized by T cells. 3. Which brings us to another paper from the disco era: Nobelists Zinkernagel and Doherty's 1974 discovery of the major histocompatibility complex (MHC) restricted nature of T-cell recognition of virus-infected cells.3 The paper initiated a huge interdisciplinary effort to understand the structural and cell biology of antigen processing and presentation to T cells. 4. Eleven years later, Unanue and colleagues solved the mystery of MHC restriction: MHC molecules bind short peptides proteolytically derived from protein antigens and present them to T cells on the surface of antigen-presenting cells.4 This finding fueled an explosion in defining the specificities of T cells specific for viral, tumor, and transplantation antigens and raised the question of how cells generate peptides from protein antigens. 5. How indeed? In linking ubiquitin conjugation to the process of ATP-dependent protein degradation, Ciechanover et al made a critical discovery that would touch nearly every aspect of cell biology, including antigen processing.5 Over the next decade, it would be shown that ubiquitin-tagged proteins are destroyed by the proteasome and that proteasome is a prime source of peptides presented to T cells by MHC class I molecules. --Jon Yewdell, Viral Immunology Laboratory, National Institute of Allergy and Infectious Diseases, National Institutes of Health References1. L.D. Frye, M. Edidin, "The rapid intermixing of cell surface antigens after formation of mouse-human heterokaryons," J Cell Sci, 7:319-35, 1970. 2. G. Kohler, C. Milstein, "Continuous cultures of fused cells secreting antibody of predefined specificity," Nature, 256:495-7, 1975. 3. R.M. Zinkernagel, P.C. Doherty, "Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system," Nature, 248:701-2, 1974. 4. B.P. Babbitt et al., "Binding of immunogenic peptides to Ia histocompatibility molecules," Nature, 317:359-61, 1985. 5. A. Ciechanover et al., "Ubiquitin dependence of selective protein degradation demonstrated in the mammalian cell cycle mutant ts85," Cell, 37:57-66, 1984.

The Jon Yewdell Selection

My Top 5 | The Jon Yewdell Selection

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