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Faculty > Faculty By Research Interest > Robert Schreiber, PhD

Alumni Professor, Pathology and Immunology
Professor, Molecular Microbiology
Office Suite C - 8417, BJCIH Building
Office: (314) 362-8747
Lab: (314) 362-8746
E-mail: schreiber@wustl.edu
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Research

Our research is aimed at elucidating the molecular cell biology of cytokine receptor signaling and in defining the effects of signaling dysfunction on tumor development. Towards these ends, we are studying the receptors for interferon-gamma (IFN„) and interleukin-10 (IL-10), two related yet distinct receptors and that regulate both the innate and adaptive limbs of the immune response, often in opposite directions. Our efforts are currently focused into three major research projects.

First, we continue our long standing analysis of IFN„ receptor signaling, which is currently at a highly advanced state. We have (a) identified and cloned the subunits of functionally active IFN„ receptors, (b) defined the critical regions present in the intracellular domains of these subunits, (c) shown that these regions function as binding sites for specific members of the JAK-STAT signaling pathway (Jak1, Jak2 and Stat1) and (d) generated and characterized mice with disruptions in the genes encoding two of the signaling pathway components i.e., Jak1 and Stat1. This work has demonstrated that most but not all of IFN„'s biologic effects on cells is mediated via the JAK-STAT signaling pathway. Presently, we are determining the nature and function of the alternative IFN„ signaling pathways we have uncovered and are defining the specific gene targets of these alternative pathways. Moreover, we are assessing the mechanisms by which the classical and alternative IFN„-dependent signaling pathways are regulated in intact cells.

Second, we have initiated a similar series of analyses on the IL-10 receptor, a receptor whose signaling mechanism is currently only poorly understood. Our recent work has shown that whereas IL-10 induces activation of the JAK-STAT signaling pathway in all IL-10 receptor bearing cells, the participation of at least one additional signaling component is required for expression of IL-10's anti-inflammatory actions on macrophages. Using PCR-based subtractive cloning procedures and gene chip technologies we have defined a novel set of IL-10 induced genes. Present work is aimed at identifying the IL-10-regulated signaling component(s) that is(are) additionally required for expression of IL-10's anti-inflammatory functions and in defining the transcription factor(s) responsible for promoting IL-10-specific gene induction.

Third, we are assessing the role of the IFN„ receptor and its signaling systems in the development of protective host anti-tumor responses. This research is based on our previous work showing that IFN„ forms the basis of an effective tumor surveillance system that provides an immunocompetent human or murine host with a mechanism to recognize and eliminate tumors that arise either spontaneously or via the actions of chemical carcinogens. At least a portion of IFN„'s effects appear to be mediated though its capacity to directly enhance tumor cell immunogenicity. Interestingly, we have also observed that tumors can become insensitive to IFN„ and thereby escape immune detection and elimination. Current work is aimed at defining IFN„'s specific roles in the tumor surveillance process, elucidating the genetic mechanisms employed by tumors to become IFN„ insensitive and exploring the relationships between IFN„ sensitivity of a tumor and its growth aggressiveness in vivo.

Selected Publications

Maldonado RA, Irvine DJ, Schreiber R, Glimcher LH. A role for the immunological synapse in lineage commitment of CD4 lymphocytes. Nature 431:527-532, 2004 Abstract

Schreiber RD, Old LJ, Hayday AC, Smyth MJ. A cancer immunosurveillance controversy. Nat Immunol 5:4-5, 2004 Abstract

Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 21:137-148, 2004 Abstract

Dunn GP, Old LJ, Schreiber RD. The Three Es of Cancer Immunoediting. Annu Rev Immunol 22:329-360, 2004 Abstract

Schreiber GH, Schreiber RD. Interferon-g.. In: The Cytokine Handbook, edited by M. Lotze and, 2003

Novack DV, Yin L, Hagen-Stapleton A, Schreiber RD, Goeddel DV, Ross FP, Teitelbaum SL. The IkapaB function of NF-kappaB2 p100 controls stimulated osteoclastogenesis. J Exp Med 198:771-781, 2003 Abstract

Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer Immunoediting: From Immunosurveillance to Tumor Escape. Nat Immunol 3:991-998, 2002 Abstract

Yin L, Wu L, Wesche H, Arthur CD, White JM, Goeddel DV, Schreiber RD. Defective Lymphotoxin-b Receptor-Induced NF-kB Transcriptional Activity in NIK-Deficient Mice. Science 291:2162-2165, 2001 Abstract

Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFN„ and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 410:1107-1111, 2001 Abstract

Gil MP, Bohn E, O'Guin AK, Ramana CV, Levine B, Stark GR, Virgin HW, Schreiber RD. Biologic consequences of Stat1-independent IFN signaling. Proc Natl Acad Sci USA 98:6680-6685, 2001 Abstract

Hanson HL, Donermeyer DL, Ikeda H, White JM, Shankaran, V, Old LJ, Shiku H, Schreiber RD, Allen PM. Eradication of Established Tumors by CD8+ T Cell Adoptive Immunotherapy. Immunity 13:265-276, 2000 Abstract

Hanson HL, Donermeyer DL, Ikeda H, White JM, Shankaran V, Old LJ, Shiku H, Schreiber RD, and Allen P. Eradication of established tumors by CD8+ T cell adoptive immunotherapy. Immunity 13:265-276, 2000 Abstract

Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KC, Yin L, Pennica D,. Disruption of the Jak1 Gene Demonstrates Obligatory and Nonredundant Roles of the Jaks in Cytokine-Induced Biologic Responses. Cell 93:373-383, 1998 Abstract

Bach EA, Aguet M, Schreiber RD. The IFNg Receptor: A Paradigm for Cytokine Receptor Signaling. Annu Rev Immunol 15:563-591, 1997 Abstract

Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber RD. Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J Biol Chem 271:27954-27961, 1996 Abstract

Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS, Kaplan DH, Riley JK, Greenlund AC, Camp. Targeted disruption of the STAT1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84:431-442, 1996 Abstract


Current Trainees

Matthew Vesely
Mark Diamond

Past Trainees

Graduate Students
Catherine Koebel

Postdoctoral Fellows
Szeman Ruby Chan, PhD