Mike Spiotto, M.D. Ph.D. student in Hans Schreiber's lab was awarded the Biological Sciences Division Award for Best Dissertation, the highest distinction for students across all the Biological Sciences Division departments and committees. Mike combined molecular biology, genetic engineering and cellular immunology to set up a new in vivo model system enabling him to simultaneously track the T cell response to a tumor and the tumor cells themselves as they mutate their antigens and escape immune rejection. He made several far-reaching observations explaining how the tumor-specific killer T cells cope with changes in concentration or affinity of tumor antigen, and illuminating the critical role of stroma in cross-presenting tumor antigens for the eradication of these tumors. Gauge of the considerable impact in the field of his work published in Immunity (Immunity. 2002 Dec;17(6):737-47) and Nature Medicine (Nature Medicine 10, 294 - 298 (2004)), his tumor rejection model is now being used in top laboratories worldwide.

Pat Burkett and Robert Chin, students of the University of Chicago MSTP program, completed their Ph.D. Thesis in Immunology this Spring with high marks from the COI Steering Committee chaired by Dr. Albert Bendelac. Pat Burkett from Averil Ma's lab elucidated unexpected contributions of the IL-15 Receptor alpha chain to the function of IL-15 in vivo (Proc. Natl. Acad. Sci. USA 100:4724-4729, 2003). Robert Chin in Yang-Xin Fu's laboratory uncovered a functional connection between lymphotoxin and autoimmunity through the induction of Aire in thymic epithelial cells (Nature Immun. 5:141-49, 2004). The COI is proud to recognize these scientific accomplishments as well as many other generous and exemplary contributions to the immunology community at the University of Chicago. Each award is accompanied by a $500 check.

Dr. Thomas Gajewski's laboratory recently has published two articles on aspects of the actin cytoskeleton, immunological synapse formation, and T cell regulation. The immunological synapse, defined as an organization of molecules at the interface between a T cell an an antigen-presenting cell, has been observed to be divided into a central supramolecular activation cluster (cSMAC) and a peripheral supramolecular activation cluster (pSMAC). Although it had been proposed that formation of a cSMAC is required for optimal T cell activation, graduate student James P. O'Keefe has shown that naïve CD8+ T cells do not form a cSMAC but yet are activated normally (PNAS reference from below). These results support the alternative model that cSMAC/pSMAC segregation may be more important for directional excocytosis by effector cells (Mol. Cell Biol., Vol. 24, 1628-1639, 2004). In a second report, graduate student Fabiola Rivas showed that actin polymerization inhibitors augment rather than block cytokine production from Th1 and Th2 cells (MCB reference from below), despite complete disruption of an immunological synapse. This effect was correlated with prolonged NFAT nuclear localization and decreased calcium export from the cell following TCR ligation. These results point to calcium signal termination as an actin-dependent process, and identify calcium export channels as potential immunoregulatory molecules (PNAS, Vol. 101, 9351-9356, 2004).

Two new faculty members joined the Committee on Immunology this Spring.

James L. Madara

Jim Madara, the Dean of Biological Sciences Division, investigates the cell biology of the intestinal epithelial cell. His laboratory has become increasingly interested in understanding the interaction of microbes with the intestinal epithelial cell and its consequences for host defense.

Aaron Dinner, Ph.D.

Dr. Aaron Dinner, Assistant Professor in the chemistry department and member of the Institute for Biophysical Dynamics http://ibd.uchicago.edu/, is developing theoretical approaches and models to understand the mechanisms of cellular dynamics. His work on the immunological synapse was recently published in Science (Science 302:1218-1222, 2003).

Megan McNerney, an MSTP COI graduate student in the laboratory of Dr. Vinay Kumar received the Best Speaker Award in the Basic Science category at the 20th International Natural Killer Cell Workshop held at Leeuwenhorst, Netherlands from April 24th to 28th. The award was based on her presentation entitled: "2B4 (CD244) acts as non-MHC binding inhibitory receptor on mouse NK cells". The inhibitory functions of 2B4 represent a novel form of self tolerance in NK cells that is not based on recognition of MHC class I molecules. The paper bearing the same title will appear in the May 3, 2004 issue of the Journal of Experimental Medicine(J. Exp. Med., 199:1245-1254, 2004). This paper has also has been choosen under the "Editors Choice: highlights of recent literature" in Science Volume 304, Number 5674, Issue of 21 May 2004 ,page 1079.

Cancer cells express antigens that are targets for specific cytotoxic T lymphocytes (CTLs) and form the basis of many new cancer vaccine approaches. However, cancer cells are genetically unstable and subpopulations of variant cells that no longer express the target antigens escape immune destruction and grow progressively. In a paper published by Nature Medicine (Nature Med. 10:294-298, 2004) Mike Spiotto, a M.D. Ph.D. student in Hans Schreiber’s lab just revealed one clever way in which this escape can be combated. Enhancing cross-presentation of cancer antigens by the tumor stroma (the non-cancerous part of the tumor) enabled CTLs to killed stromal cells, starving the cancer cells and indirectly preventing the outgrowth of antigen-loss variants. This exciting finding suggests that combining cancer vaccines with strategies enhancing presentation of tumor antigens by stromal cells may provide considerable synergy in the immunological treatment of cancer.

The American Association of Immunologists has elected Frank Fitch, Professor Emeritus in the Committee on Immunology, as the recipient of the 2004 Excellence in Mentoring Award. The Award will be conferred during a special ceremony at the annual meeting of the American Association of Immunologists in Washington DC (April-17-21, 2004). This most prestigious award honors outstanding contributions to the field of Immunology through the mentoring of trainees who have become themselves outstanding scientists. Frank, the former chairman of the COI, exemplifies the spirit of the University of Chicago Immunology community, the special emphasis on the mentor-trainee relationship and the belief that a dedicated mentor can significantly influence a trainee's successful development and career.

Marisa Alegre and colleagues, in collaboration with Paolo Puccetti and colleagues from the University of Perugia, Italy, have shown that CTLA-4, a receptor constitutively expressed by CD4+CD25+ regulatory T cells, engages the ligand B-7 on dendritic cells to induce tryptophan catabolism. In turn, these 'conditioned' dendritic cells suppress lymphocytes interacting with them through metabolic starvation. This proposed scenario suggests exciting new therapeutic approaches, for example using pharmacological inhibitors of tryptophan, in order to suppress unwanted immune responses, such as graft rejection during organ transplantation (Nature Immunol. 4:1206-12, 2003).

Mammals have three D cyclins (cyclins D1?D3), which were thought to be largely redundant. Using cyclin D3-deficient mice, Iannis Aifantis, an Assistant Professor in the COI, in collaboration with the Sicinski laboratory at Harvard University, showed that cyclin D3 specifically controlled the maturation of thymocytes into so-called CD4+CD8+ "double-positive" (DP) cells, the precursors to CD4 and CD8 T cells (Cancer Cell 4:451-61, 2003), by Sicinska and Aifantis, etc.). Furthermore, cyclin D3 deficient mice showed reduced susceptibility to T-ALL leukemias arising from immature T cells. Cyclin D3 may become a very interesting therapeutic target in human malignancies derived from immature T lymphocytes (see News and Views in the same issue of Cancer Cell 4:417-18, 2003 by Weng and Aster).

TNFa is an essential cytokine regulating inflammatory and cancer processes. Using a genetic screen, Guido Franzoso's lab recently identified Gadd45b as a pivotal mediator of the anti-apoptotic function of NF-kB in TNF signaling, which suppressed JNK signaling (De Smaele et al, Nature 2001, 414, 308-13). Now, the lab has biochemically characterized the target of Gadd45b, i.e. the intersection between NF-kB and JNK signaling, as MKK7 the activator of JNK (Nature Cell Biol. 6:146-53, 2004). This discovery has major applications for the design of specific inhibitors of inflammation and cancer.

LIGHT is a novel member of the Tumor necrosis factor family whose expression triggers upregulation of chemokines and adhesion molecules by engaging the lymphotoxin b receptor and the herpes viral entry mediator (HVEM) on stromal cells and T cells. By forcing expression of LIGHT inside tumors of mice, Dr. Ping Yu and colleagues, from the laboratory of Yang-Xin Fu, in collaboration with Dr. Hans Schreiber, a tumor immunologist at the University of Chicago, induced massive priming of anti-tumor T cells and immune rejection of tumor in situ and at distal sites (Nature Immun. 5:141-49, 2004). Converting the tumor microenvironment, usually a potent barrier against immune activation, into an inflammatory site, appears to be a crucial component of future immune therapies against cancer.

CD1 molecules are distant cousin of MHC molecules that evolved to present lipid rather than peptide antigens to T cells. The factors assisting the exchange of glycolipids between membrane bilayers and the antigen binding groove of CD1 have now been identified in a study published in Science (Science 303:523-27, 2004). First author Dapeng Zhou, a Cancer Research Institute postdoctoral fellow in the Bendelac lab, used a genetic approach to demonstrate the requirement of a family of proteins called saposins for glycolipid presentation to T cells. In collaboration with the laboratory of Dr. Luc Teyton at the Scripps Research Institute the molecular mechanism was shown to involve extraction by saposins of lipids from membranes as well as from the groove of CD1 molecules. In a Perspectives article (Science 303:485-87, 2004) in the same issue of Science, Dr. Gennaro de Libero suggested that the study initiates a new chapter in the field of antigen presentation. Albert Bendelac, the Professor and Chair of the Committee on Immunology, and co-senior author with Luc Teyton on the Science paper, indicated that the findings also had important medical implications for the design of lipid vaccines against bacteria, including the agents of tuberculosis and leprosy, and various cancers expressing tumor-specific glycolipids that can be targeted by CD1-specific T cells.

Aire is a transcription factor expressed by thymic epithelium, which appears to be crucial for immune tolerance. Using lymphotoxin b receptor deficient mice, Robert Chin and colleagues from the Yang-Xin Fu laboratory (Nature Immun. 4:1121-27, 2003) found that Aire expression was reduced. Conversely, activation of the lymphotoxin b receptor increased Aire expression. The authors concluded that Aire expression is directed by the lymphotoxin pathway in a cross-talk between thymocytes and thymic stroma that is central to immunological tolerance.

Anita Chong (Department of Surgery), Amelia Bartholomew (University of Illinois at Chicago) and Marisa Alegre (Department of Medicine) organized the 4th Great Lakes Transplant Immunology Forum that took place November 20-21 2003 at the University of Chicago. This conference annually brings together 15 laboratories with a common interest in transplantation, from 10 different universities in the Midwest. It provides an informal forum in which to present unpublished observations, discuss new ideas, identify novel research tools and models and establish exciting collaborations. The guru this year was Herman Waldmann, the Sir William Dunn Professor and Head of the Department of Pathology, University of Oxford, Oxford, Great Britain.

Tom Gajewski MD, PhD, who joined the Faculty at the University of Chicago as an Assistant Professor in 1997 with a dual appointment in the Department of Pathology and the Department of Medicine, was promoted to the rank of Associate Professor with tenure. Tom's laboratory studies the molecular and cellular regulation of T lymphocyte activation and differentiation, and in turn applies this information to preclinical and clinical efforts to promote anti-tumor immunity in vivo. The recipient of several Clinical Scientist Awards, including from the Cancer Research Institute and the Burroughs Wellcome Fund, Tom is leading the Immunology Program of the University of Chicago Cancer Center, and is actively developing and implementing tumor vaccine strategies to cure cancer patients.

Michael Nishimura, Ph.D., joined the Faculty at the University of Chicago in 2000, as an Assistant Professor in the Department of Surgery. Mike's laboratory studies T cell responses to cancer in humans and is developing new strategies of gene transfer where genes encoding potent, cancer antigen-specific T cell receptors are retrovirally expressed in the peripheral blood lymphocytes of cancer patients in order to bolster their anti-cancer immune defenses. Mike is currently the Director of the Surgical Oncology Laboratories in the Department of Surgery.

Paul Kincade, the past President of the American Association of Immunologists, was the Visiting Professor at the Annual Retreat of the Committee on Immunology, held at Lake Lawn Resort, Delavan, Wisconsin, October 10-12, 2003. Paul gave an overview of his long-standing research career and accomplishments on lymphoid progenitors, and also reported his studies on the current state of career opportunities in biological sciences (FASEB J. 2003, 17, 2169-73). Awards for the best oral presentations went to Robert Chin from the Yang-Xin Fu lab, for his talk "Lymphotoxin pathway directs thymic AIRE expression", a work just published in Nature Immunology (2003 4, 1121-1127) and Salvatore Papa from the Guido Franzoso lab, for his talk "Gadd45b mediates the NF-kB suppression of JNK signaling by targeting MKK7/JNKK2". Best poster awards went to Zara Hovhannisyan, from the Bana Jabri lab Stabilization of the DQ8/gluten peptide complex by a conserved negative charge in the CDR3 hypervariable region of the TCR, and to Megan McNerney from the Vinay Kumar lab for "A novel role of 2B4 as an inhibitor of NK cells". A Special Award was also awarded to Mona Mashayekhi, an undergraduate student in the Marisa Alegre lab for "Transplant tolerance in mice with reduced NF-kB in T cells".

Hans Schreiber received the Alexander von Humboldt Prize. The prize recognizes outstanding, career-long scientific contributions ral sciences (physics, chemistry, biology or medicine), mathematics, or humanities. Announced on September 24, 2003 at the annual meeting of the German Society for Immunology, the award will be presented by the President of the Federal Republic of Germany in Berlin in June 2004. Hans, who is a Professor in the Department of Pathology at the University of Chicago, helped establish the field of cancer antigens. His proved the existence of cancer-specific antigens encoded by somatic mutations restricted to the cancer cells. His current research, focusing on escape variants, aims at developing novel means of targeting tumor stroma to accomplish rejection of established cancers and their metastases.

Martin Weigert, the Louis Hillmann Professor of Life Sciences in the Department of Molecular Biology at Princeton University, has joined the Faculty at the University of Chicago as a Professor of Pathology andDirector of the Gwen Knapp Center for Lupus and Immunology Research. Martin's group discovered several of the basic processes underlying the generation of antibodies by B lymphocytes, including somatic hypermutation and editing. His studies on lupus, an autoimmune disease characterized by an antibody response against DNA and products of dying cells, have illuminated the mechanisms of disease and led to the generation of the first transgenic mouse models of lupus. Martin, who was recently elected to the National Academy of Sciences, is the founder and organizer of the Research Workshop on the Genetics and Mechanisms of Lupus and Autoimmunity, where top scientists gather every year to discuss cutting edge research in the field of Lupus. During the reception organized by Dean Jim Madara on November 4, 2003, Martin emphasized the important role played by the Knapps in promoting research on lupus not only at the University of Chicago, but also at the national level. Several new faculty members will be recruited to the Knapp center in coming years, in a renewed effort to understanding and treating lupus and autoimmune diseases.

Harinder Singh, Professor in Molecular Genetics & Cell Biology and Investigator of the Howard Hughes Medical Institute has been appointed a Louis Block Professor. His molecular and genetic studies of transcription factors that regulate the development and gene expression patterns of hematopoietic stem cell cells have led to seminal discoveries. In particular, Harinder’s group identified the central function of PU-1 for the generation of lymphoid and myeloid lineages. His recent work delineates functional interplays between transcription factors that control B, T and macrophage lineages.

The Saturday Seminars in Biology program, sponsored by the Biological Sciences Division, and by a series of grants from the Howard Hughes Medical Institute, provide an opportunity for 350 high school teachers and their students from Chicago and suburbs to attend lectures at the Biological Sciences Learning Center presented by faculty in the Biological Sciences Division. The Saturday Seminars in Biology meet on the third Saturday of each month throughout the school year. The first lecture of the day is open to teachers and invited students, followed by a more comprehensive lecture open only to teachers. Then, teachers have the opportunity to network with each other and discuss high school biology curriculum issues. Among the distinguished and inspirational teachers this Fall were members of the Committee on Immunology Harinder Singh, Professor in Molecular Genetics & Cell Biology and a Howard Hughes Investigator, and Barbara Kee, Assistant Professor in Pathology. Harinder gave the first lecture this year titled "Stem Cell Biology and Its Applications", a topic that dominated headlines throughout the summer. Barbara Kee lectured on the genetic processes leading to the formation of the diverse antibody repertoire.