Guido Franzoso MD, PhD, who joined the Faculty at the University of Chicago in 1997 as an Assistant Professor was promoted to the rank of Professor with tenure. Guido's laboratory has used powerful genetic approaches, including a "death trap" screen to clone genes and elucidate anti-apoptotic pathways involved in inflammation and cancer. The recipient of several awards, including the prestigious Cancer Research Institute Investigator Award, Guido holds a joint appointment in the COI and the Committee on Cancer Biology.

The Gwen Knapp Center for Lupus and Autoimmunity Research, under the direction of Dr. Martin Weigert, organized a major Symposium on the Genetic Basis of Autoimmunity at the University of Chicago Biological Science Learning Center @ 924 East 57th Street. The rostrum of international speakers included David Nemazee, Matthias Wabl, Michel Nussenzweig, Tim Behrens, Roberta Pelanda, Nina Luning Prak, Kristen Hogquist, Michael Krangel, Jeroen Roose, David Wagner, Claudia Giachino, Pam Fink and Aaron Dinner. This symposium represents a long tradition initiated by Dr Martin Weigert in the field of Lupus research, where established as well as young and upcoming investigators in the field confront new ideas and emerging technologies that carry great promise for a better understanding of the genetic, biochemical and cellular basis of lupus disease. A celebratory dinner to honor the speakers and their research efforts was organized by Gwen and Jules Knapp, major and long time supporters of the Lupus and Autoimmunity Research Center.

Marisa Alegre was awarded the unsolicited American Society of Transplantation Basic Science Career Development Award for Best Transplant Researcher at the Assistant Professor level. This prize acknowledges work performed in the Alegre laboratory on the role of positive and negative costimulatory molecules in allograft rejection and tolerance induction. The award ceremony took place at the annual American Transplant Congress in Seattle, WA, in May.

In a paper published in Cell 2004 119:529-42, the Franzoso lab identifies ferritin heavy chain as a mediator of the anti-apoptotic effects of NF?B. By sequestering iron, ferritin suppresses the accumulation of reactive oxygen species and their activation of JNK signaling. The authors propose modulation of ferritin, and more broadly iron metabolism as a novel approach for anti-inflammatory therapy.

Albert Bendelac, Professor and Chairman of the Committee on Immunology, is one of two University of Chicago scientists selected as new HHMI investigator. We are committed to providing these scientists-and the nearly 300 scientists who are already part of HHMI-with the freedom and flexibility they need in order to make lasting contributions to mankind," said Thomas R. Cech, HHMI's president. "We want and expect them to be daring." Albert Bendelac has pioneered the study of NKT cells, a conserved lineage involved in the recognition of lipid antigens presented by the MHC-like molecule CD1. NKT cells regulate a number of disease conditions through the recognition of peculiar families of glycolipids identified in the Bendelac Lab.

It is often assumed that the poor immunogenicity of tumors is due to their weak antigens, but a study by Dr. Ping Yu et al. in Yang-Xin Fu's lab now reveals the presence of CD4+ regulatory T cells inside the tumor that prevent CD8+ T cell-mediated destruction (Journal of Experimental Medicine, March 7, 2005). Local depletion of these CD4+ cells unmasked tumor immunogenicity and led to the rejection of well-established cancers, suggesting a new approach to promote the immune rejection of cancer.

NKT cells are a hybrid lineage straddling innate and adaptive immunity that regulate several infectious, inflammatory and cancer conditions. Work from Dapeng Zhou et al. in the Bendelac lab recently identified iGb3 as an agonist self ligand presented by CD1 and recognized by NKT cells (Science 306:1786-1789, 2004). Now, in a report published in Nature (Nature 434:525-529, 2005), Jochen Mattner identifies glycosylceramides in the cell wall of LPS-negative Gram-negative bacteria as potent stimulators of NKT cells. These findings suggest that the semi-invariant NKT cell TCR, which is conserved in mice and humans, evolved for dual recognition of self and microbial glycosphingolipids.

Martin Weigert, Director of the Knapp Center for Lupus and Immunology Research, was awarded the Carol-Nachman Prize, the most prestigious international award in Rheumatology research. Martin Weigert, a member of the National Academy of Sciences, has made seminal contributions to our understanding of antibody responses, including the discovery of somatic hypermutation. His laboratory has pioneered genetic approaches to model lupus and rheumatoid arthritis autoimmunity in mouse and has recently discovered Editing as a new mechanism of B cell tolerance.

Dr. Chris Borowski was awarded the Kirschstein NIH postdoctoral fellowship. Chris, a postdoctoral fellow in the Bendelac laboratory, studies the signaling mechanisms underlying the development of NKT cells. Dr. Judy Cannon was awarded a Cancer Research Institute postdoctoral fellowship. A postdoctoral fellow in the Sperling lab, Judy studies the immunological synapse.

An essential event in the development of memory CD8(+) T lymphocytes is the escape of progenitors from programmed cell death. Liu et al report in Nature Immunology (2004 5:919-26) that the gene encoding serine protease inhibitor 2A (Spi2A), an inhibitor of lysosomal executioner proteases dependent on transcription factor NF-kappaB, is upregulated in memory cell precursors. Spi2A upregulation protected lymphocytic choriomeningitis virus-specific memory progenitors from programmed cell death. These findings suggest a model in which commitment to the memory lineage is facilitated by the upregulation of protective genes.

Audrea Troutman, a graduate student in Anita Chong's lab and Luqiu Chen, a post-doctoral fellow in Marisa Alegre's lab both received a 2005 American Society of Transplantation Young Investigator Award for their work in transplantation immunology, some of which is collaborative between the 2 laboratories. Audrea studies the effect of memory B cells on the induction of tolerance to transplanted grafts and Luqiu investigates whether infections and TLR signaling prevent the induction of transplantation tolerance. Their work will be presented at the American Transplant Congress in May 2005.

The pTa complex mediates crucial functions for the survival and differentiation of early thymocytes having successfully rearranged the TCR b chain locus. Malay Mandal in the Aifantis lab has now identified the molecular underpinnings of the survival pathway mediated by pTa. BCL2A1, a new member of the Bcl-2 family, inhibited caspase 3, the executor of pre T cell apoptosis (M. Mandal et al, Journal of Experimental Medicine, 201:603-614, 2005). Furthermore, the Aifantis lab provides tantalizing evidence suggesting that excess of A1 through pTa signalling- in collaboration with dysregulated cell proliferation through cyclin D3 underlies leukemic transformation in mouse and human.

Dr. Marcus Clark, head of the Section of Rheumatology, Department of Medicine, was promoted to Associate Professor with tenure. Dr. Yang-Xin Fu, from the Department of Pathology, was promoted to Professor with tenure. Dr. Anne Sperling, from the section of Pulmonary/Critical Care, Department of Medicine, was promoted to Associate Professor with tenure.

Dr. Jose Guevara, newly appointed Assistant Professor in the Tumor Immunology Center, Department of Surgery, has developed ingenious new approaches to enhance cancer vaccines. These approaches exploit recent advances in the cell biology and the structural biology of antigen presentation by MHC molecules to the T cell receptor. Heteroclitic peptides are variants designed to enhance the potency and the specificity of the CD8 T cell response by selectively replacing certain aminoacid residues that are necessary for optimal binding to the MHC I complex. These optimized peptide variants delivered by DNA vaccination can effectively prime native CD8 T cells and induce a crossreactive response against the native tumor peptide.

NKT cells represent a hybrid lymphocyte lineage co-expressing a conserved, semi-invariant T cell receptor and receptors of the NK lineage. Their anti-cancer properties had been previously revealed by the discovery that a marine sponge glycolipid known to induce immunological rejection of cancer, alpha-galactosylceramide, could bind to the MHC-like CD1d protein and serve as a NKT cell antigen. Using a combination of genetics, cell biology and chemistry, the Bendelac lab has now identified the natural endogenous ligand of NKT cells as isoglobotrihexosylceramide (iGb3). Variations in iGb3 levels may therefore control the function of NKT cells in rejecting cancer but also in fighting infection and regulating autoimmunity. These findings, reported by Dapeng Zhou et al in Science:306, 1786-1789, 2004 represent a key advance in our understanding of the anti-cancer function of NKT cells and a potential lead into novel approaches to enhance anti-cancer immunity.

Bertrand Meresse and Zhangguo Chen in the Jabri lab report a massive expansion of cytolytic T cells (CTL) with "natural killing" properties in the gut epithelium of patients with celiac disease (so-called LAK cells by reference to lymphokine-activated-killer cells described previously in vitro). Celiac disease is a severe inflammatory bowel disease provoked by wheat gliadin in some genetically predisposed individuals. While a CD4 T cell response to wheat gluten in the lamina propria was reported previously, the intraepithelial CTL are proposed to mediate the killing of gut epithelial cells and, ultimately, villous atrophy. The Jabri lab dissected a self-amplifying loop involving the expression by diseased gut epithelium of stress-induced MIC proteins and IL-15 on one hand and, on the other hand, the aberrant induction of signaling by NKG2D, the MIC-receptor expressed on CTL, leading to direct killing of stressed tissue (Meresse, Chen et al. Immunity, 21:357-366, 2004)

Distinct sets of transcription factors and various signaling pathways are required for the specification of hematopoietic cell fates. The characterization of these gene regulatory networks and their integration with signaling pathways have represented a major challenge. Using genetic approaches to investigate the development of the B cell lineage, a leading model in developmental biology, postdoctoral fellow Kay Medina and Professor Harinder Singh have assembled what is so far the most complex regulatory network leading to cell fate specification. Their study, now published in the October issue of Developmental Cell (Dev. Cell 7:607-617, 2004) identifies a hierarchical sequence of interactions between PU1, E2A, Ikaros, EBF, and Pax5 that specifies the B cell fate. Regulatory networks of the same type but using different factors are likely to control the development of all cell lineages.

Dr. Barbara Kee was recently highlighted in the Leukemia Research Foundation (LRF) newsletter as a "scientist to watch" (http://www.leukemia-research.org/sciencewesupport.asp). Her laboratory studies the development of committed B-lymphocytes from multipotent hematopoietic progenitors, which requires the activity of numerous transcription factors including E2A, EBF, and Pax-5 as well as signals from the interleukin-7 receptor that promote survival and proliferation. A study from the Kee lab now shows that E2A coordinates the induction of transcription factors essential for both commitment and proliferation of B-lineage cells (JEM 199:1689-1700, 2004). Therefore, E2A controls multiple aspects of the B-lymphocyte development through induction of essential components of the transcriptional program.

Vinay Kumar, Professor and Chairman of the Department of Pathology, has been appointed Alice Hogge and Arthur A. Baer Professor. Dr. Kumar has made important scientific contributions to the biology of NK cells, in particular the discovery of 2B4, a membrane receptor regulating the activation of lymphocytes such as NK cells and CD8 killer cells through a novel signaling pathway. Dr. Kumar is also recognized for his leadership at the head of the Pathology Department, as well as for his contributions to the Biological Sciences Division.

Guido Franzoso MD, PhD, who joined the Faculty at the University of Chicago in 1997 as an Assistant Professor was promoted to the rank of Associate Professor with tenure. Guido's laboratory has used genetic approaches to elucidate the biochemical basis of TNF a signaling in inflammation and cancer. His discovery and characterization of the Gadd45b anti-apoptotic pathway has attracted considerable attention because of its potential applications for the design of specific inhibitors of inflammation and cancer. The recipient of several awards, including the prestigious Cancer Research Institute Investigator Award, Guido holds a joint appointment in the COI and the Committee on Cancer Biology.