Leo Lefrançois (1956–2013)

Leo Lefrancois died of a sudden cardiac event on July 20, 2013, while hiking in the Italian Dolomites with his wife and fellow immunologist, Lynn Puddington, and friends. Leo was a pioneering cellular immunologist with broad interests in CD8+ memory T cells, mucosal immunology, and gamma-delta T cell biology. He eschewed overly reductionist approaches and understood that a deep understanding of immunity would require the use of new tools with the capacity to track antigen-specific lymphocytes within hosts responding to natural infectious agents. He was therefore quick to take advantage and develop transgenic and gene-targeted mouse models, adoptive transfer of T cell receptor (TCR) transgenic T cells, and peptide:MHCI tetramers to track T cells ex vivo by flow cytometry or in situ by immunofluorescence. By studying immunity to infection, he was ahead of a field focused on immune responses to purified model antigens, and by using these tools, Leo greatly advanced the understanding of key aspects of the adaptive T cell response through many highly influential publications. Leo was one of the brightest stars of his scientific generation.Leo LefrancoisView Large Image | View Hi-Res Image | Download PowerPoint SlideLeo’s career in immunology spanned three decades. He worked as a Medical Technologist for several years after graduating with a B.S. in Microbiology and Medical Technology from Colorado State University in 1978. Close involvement with microbial and viral agents during this period likely influenced Leo’s later focus on mechanisms of immunity to infectious disease.Leo undertook Ph.D. studies in Microbiology and Immunology at Wake Forest University, where he received a Ph.D. in 1982. Working with Douglas Lyles, he studied several aspects of the cell-mediated and humoral immune responses to vesicular stomatitis virus (VSV). His characterization of antibody epitopes on the major surface glycoprotein of the virus was the basis for the study of immunity to VSV.He then pursued postdoctoral studies with Michael Bevan in the Department of Immunology at the Scripps Clinic and Research Foundation in La Jolla, CA. He studied the basic cell biology of cytotoxic T cells and characterized their heterogeneity by using the superabundant and multiform CD45 protein (then, T200)—now known to be a cell-surface phosphatase. He also clarified the role that CD8+ T cells play in allograft rejection. These studies were described in a remarkable 11 first or last author publications.Leo then took a position as a Research Scientist in the Department of Cell Biology at The Upjohn Company in Kalamazoo, MI, and worked there until 1991. During his time at Upjohn, Leo changed his research emphasis entirely and carried out pioneering work on gamma-delta T cells. It was here that Leo initiated his long interest in the mucosal immune system, and he found that intestinal epithelial lymphocytes largely expressed the gamma-delta T cell antigen receptor. It is a testament to Leo’s persuasiveness that a 100-year-old pharmaceutical company known for cortisone synthesis allowed his work on T cell subsets found within mouse gut epithelium. These early Lefrancois studies set the stage for a series of highly cited papers showing that the anatomic location of gamma-delta T cells influences their function in part as a consequence of exposure to commensal microbes. His work on gamma-delta T cells culminated with the recent discovery of the means to elicit protective memory in gut gamma-delta T cells.Leo changed direction again in 1992 when he took a position as an Associate Professor at the University of Connecticut Health Center. Here his already stellar career accelerated as he focused on the alpha-beta CD8+ T cell response to infection. In a now classic study, Lefrancois and then graduate student David Masopust showed that peptide:MHCI-specific CD8+ T cells induced by viral or bacterial infection are primed in secondary lymphoid organs and then migrate in large numbers to nonlymphoid tissues. Furthermore, the CD8+ memory T cells present in nonlymphoid tissues were more cytolytic than the ones with the same peptide:MHCI-specificity in the spleen. By revealing the existence of nonlymphoid CD8+ effector-memory T cells positioned for immediate response to the inducing infection, this seminal work laid the groundwork for current investigations of tissue-resident memory cells and vaccine strategies aimed at generating this population. Now that this one Science article has been cited more than 1,000 times, it is easy to forget how ignored the nonlymphoid lives of T cells were before Leo’s work. Leo’s studies on the peptide:MHCI-specific CD8+ T cell response to oral infection with Listeria monocytogenes also highlighted the important roles that CD8+ memory T cells and dendritic cells play in the intestinal mucosa.Leo’s group made seminal contributions to the current understanding of CD8+ T cell survival and homeostasis. In another highly cited study, Leo and colleagues demonstrated the importance of the cytokine interleukin-7 (IL-7) in maintaining the interphase survival of naive and memory T cells. They went on to show that IL-7 could drive the proliferation of naive and memory T cells in lymphopenic hosts. The knowledge that IL-7 is a key survival cytokine for T cells is now being used to speed immune reconstitution in patients who have undergone cytotoxic regimens. His group also showed that IL-15 was important for the generation and the subsequent maintenance of CD8+ memory T cells induced by virus infection.Like many investigators, Leo used the method of transferring T cells from TCR transgenic T cells into adoptive hosts to study the in vivo immune response of antigen-specific naive T cells. In a 2005 report, however, Leo established an important concept in experimental immunology. He and colleagues showed that transferring a million monoclonal CD8+ T cells into a host caused intraclonal competition and a skewed immune response. These results have important implications with respect to the differentiation of effector and memory precursor cells and explicitly pointed out the need to do more physiologically relevant experiments involving fewer transferred monoclonal T cells. Leo followed his own lead, recently doing insightful experiments that revealed the differentiation of single naive T cells.Leo’s scientific contributions were recognized by his election to the American Association for the Advancement of Science and the Connecticut Academy of Science and Engineering and invitations to give prestigious lectures, including the Grand Marnier Foundation Guest Scientist in Residence at the Pasteur Institute in Paris and the Daisuke Nakada Memorial Lecture at the University of Pittsburgh. Leo gave back to the community through service to the American Association of Immunologists, the Society for Mucosal Immunology, and the American Society for Microbiology. He served as an Associate Editor for the Journal of Immunology from 1990 to 1994 and as a Section Editor from 1995 to 2000.Leo was a basic scientist, and we know that he wanted to be judged as one. A simple test of the importance of a basic scientist’s work comes from the thought experiment of what it would be like to teach their discipline without their contributions. What would it be like to teach modern immunology if we did not know that effector T cells migrate to nonlymphoid organs after activation, that T cells are maintained by IL-7, and that gamma-delta T cells are abundant in epithelial layers? These important discoveries will contribute to the education of immunology students around the world. There is no doubt that the field is poorer for Leo’s passing as his scientific productivity and influence were still ascending. We will remember Leo as the quintessential cellular immunologist, a wonderful colleague, and a sincere friend. He was a man of many interests, both scientific and nonscientific, and he enjoyed sharing those interests with friends and colleagues. He was serious about his work but lacked interest in self-promotion. These qualities motivated his students and endeared him to his peers. If we can find any consolation in his death, it is the knowledge that he died living his life to the fullest, doing something that he loved in the company of his wife and friends. Although his scientific legacy will live on, we will miss him greatly.