Th1 or Th17 Cells: What are the Pathogenic T cells in CNS Autoimmunity?
Posted July 02, 2007
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Overview
For years, immunologists thought that Th1 cells were primarily responsible for autoimmune conditions such as multiple sclerosis and inflammatory bowel disease. But when mouse geneticists knocked out the gene encoding interferon-γ, which is required for Th1 cell development, they discovered that mice lacking Th1 cells could still develop autoimmune disease. Subsequent work uncovered a previously unknown helper T cell lineage, dubbed Th17 cells, which researchers now hypothesize may be responsible for autoimmunity.
A March 22, 2007, meeting of the Academy's Neuroimmunology Discussion Group addressed the resulting question: Is autoimmunity caused by Th1 cells or Th17 cells? Researchers looked at the role of various cytokine signaling pathways—including TGF-β, IL-6, IL-23, interferon-γ, and IL-17—in defining the fates of T cells, and how pushing the cells to one T-cell type or another affected the appearance of disease in mouse models. Speakers also discussed evidence that the nuclear hormone receptor RORγt may sit at the base of both the Th17 and Treg pathways, serving as the decision point between inflammation and suppression.
Use the tabs above to find a meeting report and multimedia from this event.
Web Sites
Crohn's Disease
This Web site, by the National Digestive Diseases Information Clearinghouse, details the symptoms of the disease, treatment, and current research.
MedlinePlus: Crohn's Disease
This Web site has the basics of Crohn's Disease, as well as many links for additional information.
Multiple Sclerosis: National Institute of Neurological Disorders and Stroke
This Web site contains information about the disease, current clinical trials, and links to other organizations for people with multiple sclerosis.
National Multiple Sclerosis Society
The National MS Society funds multiple sclerosis research, provides services to people with MS, offers professional education, and serves as an advocacy group for people with the disease.
National Psoriasis Foundation
This Web page details the immune system involvement in psoriasis in layman's terms.
Articles
Th1 vs. Th17 Cells in CNS Autoimmunity
Bettelli E, Oukka M, Kuchroo VK. 2007. T(H)-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8: 345-350.
Carrier Y, Yuan J, Kuchroo VK, Weiner HL. 2007. Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-β T cell-transgenic mice. J. Immunol. 178: 179-185.
Deaglio S, Dwyer KM, Gao W, et al. 2007. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. May 14; [Epub ahead of print]
Korn T, Reddy J, Gao W, et al. 2007. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat. Med. 423-431.
Veldhoen M, Hocking RJ, Atkins CJ, et al. 2006. TGF-β in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24: 179-189.
Regulation of Th1 and Th17 Cells
Kleinschek MA, Owyang AM, Joyce-Shaikh B, et al. 2007. IL-25 regulates Th17 function in autoimmune inflammation. J. Exp. Med. 204: 161-170.
McGeachy MJ, Cua DJ. 2007. T cells doing it for themselves: TGF-β regulation of Th1 and Th17 cells. Immunity 26: 547-549.
Sato K, Suematsu A, Okamoto K, et al. 2006. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203: 2673-2682. Full Text
Xiao H, Gulen MF, Qin J, et al. 2007. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26: 461-465.
Effector CD4 T cells During Chronic Inflammation: Trust Your Gut
Hatton RD, Harrington LE, Luther RJ, et al. 2006. A distal conserved sequence element controls Ifng gene expression by T cells and NK cells. Immunity 25: 717-729.
Mangan PR, Harrington LE, O'Quinn DB, et al. 2006. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441: 231-234.
Weaver CT, Harrington LE, Mangan, et al. 2006. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24: 677-688.
Weaver CT, Hatton RD, Mangan PR, Harrington LE. 2007. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25: 821-852.
Role of RORγ-t in Immune System Homeostasis
Eberl G, Marmon S, Sunshine MJ, et al. 2004. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5: 64-73. (PDF, 2.53 MB) Full Text
Ivanov II, Diehl GE, Littman DR. 2006. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126: 1121-1133.
Lopes JE, Torgerson TR, Schubert LA, et al. 2006. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J. Immunol. 177: 3133-3142.
Niess JH, Brand S, Gu X, et al. 2005. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307: 254-258.
Speakers
Vijay Kuchroo, PhD
Harvard Medical School
e-mail | web site | publications
Vijay Kuchroo is a professor of neurology at Harvard and an associate immunologist at the Brigham and Women's Hospital in Boston. Born in Kashmir, India, Vijay Kuchroo initially trained as a veterinarian before pursuing basic research. After receiving a PhD in pathology from the University of Queensland, Australia in 1985, he came to the U.S. National Institutes of Health as a Fogarty International Fellow, then joined the faculty at Harvard Medical School.
An author on more than 100 original research papers and numerous review articles, Kuchroo also sits on several editorial and grant-review boards. He has also received numerous honors, including the Fred Z. Eager Research Prize for his work at the University of Queensland, and the Javits Neuroscience Award from the National Institutes of Health in 2002. Kuchroo's current work focuses on the genetics and molecular biology of autoimmune diseases, especially type 1 diabetes and multiple sclerosis.
Daniel Cua, PhD, MD
Schering-Plough Biopharma
e-mail | publications
Daniel Cua has been with DNAX Research Institute, a division of Schering-Plough Research Institute, since 2000. As senior principal scientist of discovery research, his responsibilities include in vivo target validation of novel cytokines for regulating immune-mediated inflammatory disorders. His research papers have appeared in journals such as Cell, Immunity, Nature Immunology, Annual Review of Immunology, Journal of Experimental Medicine, and Journal of Clinical Investigation. In 2003, his work appearing in the journal Nature provided definitive proof that IL-23 is a critical cytokine that promotes autoimmune inflammatory disorders. This seminal finding led to the development of the IL-23/Th17 immune axis hypothesis. His team has filed several invention disclosures and he is principal inventor or co-inventor for five patent applications.
Cua completed his doctorate in 1997 with the Department of Molecular and Cellular Immunology at University of Southern California School of Medicine.
Laurie Harrington, PhD
University of Alabama at Birmingham
e-mail | web site | publications
Laurie Harrington is a postdoctoral fellow in the laboratory of Casey Weaver at the University of Alabama at Birmingham. After graduating with departmental honors in medical laboratory science from the University of Vermont, Laurie Harrington moved to Atlanta for doctoral studies in immunology at Emory University.
Though still at an early stage of her career, Harrington has already established an impressive record in her field, including 15 research publications and a score of presentations and abstracts at international meetings. She has also received several awards, including an AAI-Huang Foundation Trainee Achievement Award in 2005, and appointment as a FOCIS Trainee Satellite Symposium representative in 2006. Her work focuses on the regulation of T cell maturation and the development of autoimmunity, especially in Crohn's disease and inflammatory bowel disease.
Dan Littman, PhD, MD
Skirball Institute of Biomolecular Medicine, New York University
e-mail | web site | publications
Daniel Littman is the Helen L. and Martin S. Kimmel Professor of Molecular Immunology and Professor of Pathology and Microbiology at the Skirball Institute of Biomolecular Medicine at New York University School of Medicine, where he directs the Molecular Pathogenesis Program. Littman is a also a Howard Hughes Medical Institute Investigator. He was formerly Professor of Microbiology and Immunology at the University of California, San Francisco. He holds MD and PhD degrees from Washington University in St. Louis.
Littman's research interests are in the areas of T lymphocyte development, lymphoid organogenesis, and HIV pathogenesis. He has applied mouse genetic approaches towards gaining insights into each of these areas. His contributions have led to new therapeutic approaches for AIDS and autoimmune diseases. Littman is a Fellow of the American Academy of Arts and Sciences and is a Member of the National Academy of Sciences. He was awarded the 2004 New York City Mayor's Award for Excellence in Science and Technology.
Alan Dove
Alan Dove is a science writer and reporter for Nature Medicine, Nature Biotechnology, and Bioscience Technology. He also teaches at the NYU School of Journalism, and blogs at http://dovdox.com.