 Ph.D. University of London 1984 MB BS University of London 1978
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Nick
Crispe
Associate Director, Center for Vaccine Biology and Immunology Professor of Microbiology and Immunology and of Medicine Primary Academic Appointment: Center
Affiliation: GEBS
Cluster Affiliations: |
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| Contact Information | ||
| University
of Rochester School of Medicine and Dentistry 601 Elmwood Ave, Box 609 Rochester, New York 14642 | Phone:
(585) 273-1400 E-Mail: nick_crispe@urmc.rochester.edu |
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- Research Focus
- Development, Activation and Death of T lymphocytes
- Research Overview
- My lab studies immunology with a focus on T cells. We have a major research program in the interaction of T cells with the liver, where the majority of our work is in the mouse but we also collaborate with clinical researchers in hepatology and transplantation. Our other area is the cell cycle biology of T cells and their precursors, which leads us to be interested in hematopoietic stem cells.
- In the liver, our main questions are: (1) How are T cell activated by antigens from the liver parenchyma, and in what ways does the unique immunological environment of the liver explain that organ’s immune privilege? (2) How does the liver regulate systemic immunity? (3) How do T cells interact with other liver cells in chronic liver disease? To approach the first question we have optimized a gene delivery system based on adeno-associated virus vectors, and find that hepatocellular antigens effectively activate CD8+ but not CD4+ T cells. This may be due to a local defect in cross-presentation. In parallel we have used liver transplantation in mice to limit antigen presentation to the liver, and these experiments also reveal CD8+ T cell activation. Now we want to identify the antigen presentation and co-stimulatory pathways engaged by T cells responding to hepatocellular antigens, and determine whether this explains the liver’s immune privilege. Understanding these mechanisms is important not only in transplantation, but for chronic liver infections such as HCV.
- The liver sequesters activated CD8+ T cells from the circulation, and we have identified many of the molecules involved in their trapping (ICAM-1, VCAM-1, TLR-4) and death (TNF-alpha). We now want to clarify the molecular pathways responsible for the process, and in particular the nature of TLR-4’s involvement. We also have evidence that intrahepatic CD8+ T cell localization regulates the magnitude of both primary and secondary immune responses, so it is imperative to determine how important this is in systemic immunoregulation and memory T cell biology. Since we have worked extensively on liver T cells, we are in a good position to develop mouse models of chronic viral hepatitis, and to explore the links between immune events and fibrosis.
- Our cell cycle biology program addresses the molecular basis of T cell and stem cell self-renewal, differentiation and death. We take as our point of access the E2F transcription factors, which are central in cell cycle progression but also linked to differentiation and apoptosis. Thus, we have shown that the susceptibility of T cells to death receptor-induced apoptosis is linked to the G1 phase, and established that this works through induction of apoptotic signaling molecules under the control of E2F-1. In hematopoietic progenitors, we are interested in the action of E2F-4 in promoting differentiation from stem cells to common lymphoid progenitors, T cells and B cells. Ultimately we would like to identify the molecular links between the cell cycle control proteins, such as the E2F factors, and stem cell and lymphocytes differentiation events.
- Research Papers
- Enos ME, Bancos SA, Bushnell T, Crispe IN E2F4 modulates differentiation and gene expression in hematopoietic progenitor cells during commitment to the lymphoid lineage. J Immunol. 2008 Mar 15;180(6):3699-707
- Tu Z, Bozorgzadeh A, Pierce RH, Kurtis J, Crispe IN, Orloff MS "TLR-dependent cross talk between human Kupffer cells and NK cells." J Exp Med. 2008 Jan 14;
- Klein I, Cornejo JC, Polakos NK, John B, Wuensch SA, Topham DJ, Pierce RH, Crispe IN "Kupffer cell heterogeneity: functional properties of bone marrow derived and sessile hepatic macrophages." Blood. 2007 Dec 1;110(12):4077-85
- Klein I, Gassel HJ, Thiede A, Crispe IN, Steger U "A microsurgical approach to hepatic and extrahepatic antigen presentation and its effects on the migration pattern of activated CD8(+) T cells." Microsurgery. 2007;27(4):289-94
- Azadniv M, Dugger K, Bowers WJ, Weaver C, Crispe IN "Imaging CD8+ T cell dynamics in vivo using a transgenic luciferase reporter." Int Immunol. 2007 Aug 14;
- Klein I, Cornejo JC, Polakos NK, John B, Wuensch SA, Topham DJ, Pierce RH, Crispe IN "Kupffer cell heterogeneity: functional properties of bone marrow-derived and sessile hepatic macrophages." Blood. 2007 Aug 9;
- Polakos NK, Klein I, Richter MV, Zaiss DM, Giannandrea M, Crispe IN, Topham DJ "Early Intrahepatic Accumulation of CD8+ T Cells Provides a Source of Effectors for Nonhepatic Immune Responses." J Immunol. 2007 Jul 1;179(1):201-10
- Tu Z, Bozorgzadeh A, Crispe IN, Orloff MS "The activation state of human intrahepatic lymphocytes." Clin Exp Immunol. 2007 May 18;
- John B, Klein I, Crispe IN. "Immune role of hepatic TLR-4 revealed by orthotopic mouse liver transplantation." Hepatology. 2006 Dec 22;45(1):178-186
- Klein I, Gassel HJ, Crispe IN Cytotoxic T-cell response following mouse liver transplantation is independent of the initial site of T-cell priming. Transplant Proc. 2006 Dec;38(10):3241-3
- Crispe IN, Giannandrea M, Klein I, John B, Sampson B, Wuensch S. "Cellular and molecular mechanisms of liver tolerance." Immunol Rev. 2006 Oct; 213:101-18.
- Wuensch SA, Pierce RH, Crispe IN "Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation." J Immunol. 2006 Aug 1;177(3):1689-97
- Polakos NK, Cornejo JC, Murray DA, Wright KO, Treanor JJ, Crispe IN, Topham DJ, Pierce RH "Kupffer cell-dependent hepatitis occurs during influenza infection." Am J Pathol. 2006 Apr;168(4):1169-78; quiz 1404-5.
- Klein
I, Crispe IN. "Complete
differentiation of CD8+ T cells activated locally within the
transplanted liver." J Exp Med. 2006 Feb 20;203(2):437-47. Epub 2006 Feb 13. - Wright KO, Murray DA, Crispe NI, Pierce RH. "Quantitative PCR for detection of the OT-1 transgene." BMC Immunol. 2005 Aug 24;6:20.
- John B, Crispe IN. "TLR-4 regulates CD8+ T cell trapping in the liver." J Immunol. 2005 Aug 1;175(3):1643-50.
- Murray DA, Crispe IN. "TNF-alpha controls intrahepatic T cell apoptosis and peripheral T cell numbers." J Immunol. 2004 Aug 15;173(4):2402-9.
- Cao, Q., Y. Xia, et al. "The E2F-1 transcription factor promotes caspase-8 and bid expression, and enhances Fas signaling in T cells." J Immunol 173(2): 1111-7, 2004.
- John B, Crispe IN. Passive and active mechanisms trap activated CD8+ T cells in the liver. J Immunol. 172:5222-9, 2004.
- Laouar Y, Crispe IN, Flavell RA. Overexpression of IL-7R alpha provides a competitive advantage during early T-cell development. Blood 103:1985-94, 2004.
- Huleatt JW, Cresswell J, Bottomly K, Crispe IN. P27kip1 regulates the cell cycle arrest and survival of activated T lymphocytes in response to interleukin-2 withdrawal. Immunology 108:493-501, 2003.
- Klugewitz K, Blumenthal-Barby F, Schrage A, Knolle PA, Hamann A, Crispe IN. Immunomodulatory effects of the liver: deletion of activated CD4+ effector cells and suppression of IFN-gamma-producing cells after intravenous protein immunization. J Immunol. 169:2407-13, 2002.
- Review Articles
- Topham DJ, Crispe IN. Contrasting urban and rural lifestyles of memory CD8+ T cells. Immunity 18:584-6, 2003.
- Crispe IN. Hepatic T cells and liver tolerance. Nat Rev Immunol.3:51-62, 2003.
- Park S, Murray D, John B, Crispe IN. Biology and significance of T-cell apoptosis in the liver. Immunol Cell Biol. 80:74-83, 2002.
- Mehal WZ, Azzaroli F, Crispe IN. Immunology of the healthy liver: Old Questions and New Insights. Gastroenterology 120:250-260, 2001.
- Crispe IN, Dao T, Klugewitz K, Mehal WZ, Metz DP. The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev. 174:47-62, 2000.
- Crispe IN. Do natural T cells promote liver regeneration? Hepatology 31:1022-4, 2000.
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